Detoxification and Cleansing Programs

Body Detox Made Easy

Body Detox Made Easy

What exactly is a detox routine? Basically a detox routine is an all-natural method of cleansing yourbr body by giving it the time and conditions it needs to rebuild and heal from the damages of daily life and the foods you eat and other substances you intake. There are many different types of known detox routines.

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Scope of Drug Metabolism toward Xenobiotic Detoxification

Over the course of evolution organisms were exposed to environmental compounds of negligible nutritive value. These have variably been called 'foreign compounds' or 'xenobiotics.' Also the term 'drug' is used for them in contrast to the narrower term 'therapeutic drug' to specifically designate those xenobiotics that are intended for clinical use. Organisms that developed systems enabling them to get rid of these xenobiotics before they could accumulate to toxic levels had an evolutionary advantage. Such systems therefore had an obvious scope toward detoxification.1 A further need was the ability to detoxify 'future unknowns.' Therefore, the enzymes exclusively or predominantly catalyzing the metabolism of xenobiotics usually (1) have a very broad substrate specificity and (2) exist in large families or superfamilies of enzymes each one of them possessing a broad but distinct substrate specificity, which in part overlaps with the specificities of the other isoenzymes.1 The...

The Phase Concept of Drug Metabolism and Its Importance for Toxification versus Detoxification

The phase concept of drug metabolism is described elsewhere in this book (see 5.05 Principles of Drug Metabolism 1 Redox Reactions 5.06 Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions). With respect to toxification versus detoxification it is important that depending on their chemical nature the functional groups introduced in the phase I of drug metabolism can be classified as electrophilic or nucleophilic (Figure 1). Functional groups with an electrophilic carbon are, for example, epoxides or a,b-unsaturated carbonyl groups. Nucleophilic substituents are, for example, hydroxyl, amino, sulfhydryl, or carboxylic groups. Owing to their ability to react with electron-rich substituents in important intracellular steering molecules such as proteins and nucleic acids, electrophilic metabolites can depending on their individual chemical reactivity - be highly cyto-toxic and or mutagenic. Nucleophilic metabolites, however, usually do not covalently modify endogenous...

Toxification versus Detoxification

The key point is that a given species was not able to 'predict' what kind of xenobiotics it would be exposed in future since the organisms and their constituents in its environment obviously also underwent evolutionary changes. Thus, excretory systems of low specificity and hence high flexibility provided an evolutionary advantage. However, there was a price to pay for this flexibility. The low substrate specificity of the enzymes catalyzing the reactions allowing for a vast array of 'unforeseen' lipophilic xenobiotics to ultimately be converted to metabolites sufficiently hydrophilic for excretion quite frequently led to toxic intermediary metabolites.1 Therefore, drug metabolism leads to both detoxification and toxification. Indeed, practically all drug-metabolizing enzymes that have been investigated so far play dual roles detoxification and toxification. However, for individual structural elements of a given drug it becomes increasingly possible to predict whether a given enzyme...

Vegetables and Fruits

Vegetables and fruits are the cornerstones of a healthy diet. They are rich sources of vitamins, minerals, complex carbohydrates, and fiber. Some, such as peas and corn, are also good sources of protein. Moreover, vegetables and fruits are generally inexpensive, contain no cholesterol, have little or no fat, and are low in calories. A high intake of vegetables, particularly of the Brassica family (broccoli, cabbage, cauliflower, and Brussels sprouts) can sharply reduce the risk of cancer.10 These vegetables contain compounds that can help the body detoxify and clear potential carcinogens. In addition, fruits and vegetables are rich sources of antioxidant nutrients, such as beta carotene and vitamin C, that may also protect against cancer and heart disease.21,22

The Neurobiology of Substance Dependence

Brain abnormalities resulting from chronic use of nicotine, stimulants, opioids, alcohol, hallucinogens, inhalants, cannabis, and many other abused substances are underlying causes of dependence (the need to keep taking drugs to avoid a withdrawal syndrome) and addiction (intense drug craving and compulsive use). Most of the abnormalities associated with dependence resolve after detoxification, within days or weeks after the substance use stops. The abnormalities that produce addiction, however, are more wide-ranging, complex, and long-lasting. They may involve an interaction of environmental effects for example, stress, the social context of initial opiate use, and psychological conditioning and a genetic predisposition in the form of brain pathways that were abnormal even before the first dose of opioid was taken. Such abnormalities can produce craving that leads to relapse months or years after the individual is no longer opioid-dependent.

Therapeutic Potential Of Nscs

The inherent biologic properties of NSCs may circumvent limitations of other techniques for treating metabolic, degenerative, or other widespread lesions in the brain. They are easy to administer (often directly into the cerebral ventricles), are readily engraftable, and circumvent the blood-brain barrier. Unlike BMT, a preconditioning regime is not required before administration (e.g., total-body irradiation). One important property of NSCs is their apparent ability to develop into integral cytoarchitectural components (47) of many regions throughout the host brain as neurons, astrocytes, oligodendrocytes, and even incompletely differentiated, but quiescent, progenitors. Therefore, they may be able to replace a range of missing or dysfunctional neural cell types. A given NSC clone can give rise to multiple cell types within the same region. This is important in the likely situation where return of function may require the reconstitution of the whole milieu of a given region, e.g.,...

Glutathione Sconjugates

Thus, the 10,11-epoxide and the 10,11-dihydrodiol are urinary metabolites in humans and rats given the drug. In epileptic patients, the range of plasma concentrations of the epoxide and the diol was approximately 0.8-17 mM and 0.8-36 mM, respectively, i.e., a predominance of the latter.33 A number of studies have also addressed the origin of toxic reactions seen in some patients, e.g., CNS symptoms, gastrointestinal and hepatic disturbances, and hypersensitivity. Whereas no single factor seems to account for such toxic effects, the pharmacologically active 10,11-epoxide appears to contribute to clinical toxicity.34 In this perspective, the EH-catalyzed hydrolysis of the epoxide appears as a reaction of detoxification.

Figure 15 Structure of the cofactor uridine5diphosphoaDglucuronic acid 39 UDPGA generic reactions of O and

An important pathway of O-glucuronidation is the formation of acyl-glucuronides (Figure 15a). Substrates are numerous nonsteroidal anti-inflammatory arylacetic and 2-arylpropionic acids (e.g., ketoprofen, 43 in Figure 16) and aliphatic acids (e.g., valproic acid, 44 in Figure 16). More recent drug classes such as statins and endothelin receptor antagonists may also yield acyl-glucuronides. Aromatic acids do not appear to be good substrates, but there are exceptions. The significance of acyl-glucuronides has long been underestimated. Indeed, these metabolites are quite reactive, rearranging to positional isomers and binding covalently to plasma and seemingly also tissue proteins.84,85 Thus, acyl-glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxification.

Trends In Treatment And Prevention

Detoxification became prevalent in the mid-1900s. Public detoxification facilities, established first in Eastern Europe, spread throughout the world. For many patients, this resource offers an entree into recovery. For others, revolving door detoxification may actually produce lifelong institutionalization on the installment plan (Gallant et al., 1973). The problem of the treatment-resistant public inebriate exists today in all parts of the United States. More sophisticated methods of pharmacotherapy have appeared recently, although these remain few in comparison with other areas of medicine. Safe detoxification is possible through increased basic and clinical appreciation of withdrawal syndromes. Disulfiram, naltrexone, buprenorphine, and methadone may be selectively prescribed as maintenance drugs in the early difficult months and years of recovery. Other medications are currently being investigated for use in special circumstances.

Conjugations with Glutathione 506371 Glutathione and glutathione transferases

Glutathione (64, Figure 22 GSH) is a thiol-containing tripeptide of major significance in the detoxification of drugs and other xenobiotics. In the body, it exists in a redox equilibrium between the reduced form (GSH) and an oxidized form (GSSG). The metabolism of glutathione (i.e., its synthesis, redox equilibrium, and degradation) is quite complex and involves a number of enzymes.112-115 Glutathione reacts in a variety of ways, one of which is its redox capacity. Indeed, GSH can reduce peroxides (a reaction catalyzed by glutathione peroxidase) and organic nitrates in its GSSG form, glutathione can oxidize the superoxide anion radical. Of major significance in detoxification reactions is the capacity of GSH (and other endogenous thiols including albumin) to scavenge free radicals, in particular radical oxygen species (e.g., R, HO, HOO, ROO). As such, glutathione and other thiols have a critical role to play in cellular protection.116 The reactions involved are highly complex and can...

Substrates of glutathione transferases

Quinones (ortho- and para-) and quinoneimines are structurally very similar to a,b-unsaturated carbonyls. They react with glutathione by two distinct and competitive routes, one of which is a reduction to the hydroquinone or aminophenol, where GSH does not react covalently with the substrate but emerges in the oxidized form (GSSG). The other route is relevant to the present context, being a nucleophilic addition to form a conjugate. The reaction has physiological significance since endogenous metabolites such as quinone metabolites of estrogens are conjugated to glutathione. A medicinal example is provided by the toxic quinoneimine metabolite (71, Figure 23 see 5.05 Principles of Drug Metabolism 1 Redox Reactions 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs) of paracetamol (30). Its glutathione conjugate (71) is not excreted as such in humans dosed with the drug, but as the mercapturic acid (67, Figure 22). The reaction is one of major...

Multiplicity and ligand specificity

Which are bioactivated byAOX (orXOR). AOXalso plays an important role in the detoxification of potentially reactive iminium ions that can be generated by P450 or MAO, often from cyclic tertiary amines, e.g., nicotine.40 Menadione, isovanillin, and raloxifene are useful diagnostic inhibitors of AOX.65

Tissue distribution and ontogenic development

The ontogeny of SULTs was studied recently by Richard et al xz in the developing liver, lung, and brain. SULT1A1 enzymatic activity was higher in fetal tissues than in postnatal liver. Also SULT1A3 was expressed at higher levels in early stages of development, decreased gradually in the late fetal early neonatal liver and was not observed in adult liver. In the lung, high SULT1A3 activity was observed in the fetus compared to neonatal levels. Therefore, the developing fetus clearly possesses significant sulfation capabilities. This could be a consequence of the important role sulfation plays in the homeostasis of hormones and other endogenous compounds that are important for development or because of the need for xenobiotic detoxification in the fetus where other conjugating enzymes, notably the UGTs, are not expressed at high levels until the neonatal stage.

Monoamine oxidases MAOs EC 1434

(MPTP) is an interesting example of metabolism-related selective toxicity. It is toxified via the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium salt (MPDP +) to the 1-methyl-4-phenyl pyridinium salt (MPP+). MPP+ is taken up by a high-affinity reuptake system specifically localized in the nigrostriatal dopaminergic neurons and blocks their mitochondrial energy metabolism. This leads to death of these neurons, which causes Parkinson's disease. Within the neurons only MAO can metabolize MPTP, while in other tissues CYP- and FMO-catalyzed detoxification reactions compete with MAO for the substrate. This combination of selective uptake into cells possessing a selective pattern of drug-metabolizing enzymes causes the selective neurotoxicity. MPTP is an experimental chemical. Related compounds such as beta-carboline or tetrahydroisoquinoline are present at low concentrations in food. Whether they behave in a similar way to MPTP and therefore are neurotoxicologically important by...

Dehydrogenases and reductases

Alcohol dehydrogenase (E.C. 1.1.1) (ADH)32 toxifies ethanol to acetaldehyde, which is then (predominantly) detoxified by an aldehyde dehydrogenase (E.C. 1.2.1) to acetic acid. The second step, the aldehyde dehydrogenase-mediated oxidation to acetic acid, is inhibited by disulfiram (Antabus), which is used in the treatment of alcohol addiction. After alcohol consumption disulfiram leads to the accumulation of the toxic acetaldehyde. The resulting toxicity provokes headache and nausea, which is intended to keep the alcoholic from further alcohol consumption. Many other aldehydes, such as the a,b-unsaturated aldehydes (lipid peroxidation products), are also markedly toxic. Thus, aldehyde dehydrogenase predominantly leads to detoxification. However, as is the case with all adequately investigated drug-metabolizing enzymes, aldehyde dehydrogenase plays a dual role with respect to toxification detoxification, the nature of which depends on the substrate in question. Methanol is metabolized...

UDPglucuronosyltransferases EC 24117

Conjugation with glucuronic acid is the most abundant phase-II reaction (see 5.06 Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions). UDP-glucuronosyltransferases (UGTs)52 catalyze the formation of beta-D-glucuronides from a large variety of xenobiotics by their reaction with UDP-glucuronic acid (UDPGA). Hydroxyl-, thiol-, amino-, hydroxylamino- and carboxyl-substituents serve as the anchor to which glucuronic acid can be conjugated (also C-glucuronides can be formed if the hydrogen of the respective C-H bond is sufficiently mobile such as a carbon atom between two carbonyl functions). The xenobiotic substituents engaged in the glucuronic acid conjugation are nucleophilic. Accordingly, the majority of the UGT substrates are not genotoxic. The anchor groups listed above are often determinants or co-determinants of the biological activity of drugs and toxins, since they are frequently involved in the interaction with receptors or enzymes. Therefore, conjugation of...

Sulfotransferases EC 282

Sulfotransferases (SULTs)55 catalyze the transfer of a sulfonyl group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to nucleophilic substituents of their substrates, analogous to the UGTs. Accordingly, SULTs are often detoxifying enzymes for the same reasons discussed above for the UGTs. On the other hand, sulfoconjugation is in a predictable fashion also an important toxification mechanism for several types of precarcinogens.55,56 Aromatic hydroxylamines, metabolically produced from aromatic amines by CYP, are metabolized by SULT to aromatic N-O-sulfate esters, which heterolytically decompose to the sulfate anion and to the genotoxic nitrenium ions. Sulfation of benzylic alcohols leads to the formation of reactive carbenium ions after cleaving off the sulfate group. Thus, mice with SULTs have a substrate spectrum similar to that of the UGTs, except they do not conjugate carboxylic acids. Generally, SULTs have a lower Km than UGTs. Hence, an important detoxification function of...

Acetyltransferases included in EC 231

Since, in contrast to most phase II reactions of drug metabolism, the metabolites of NAT reactions (typically amides) are usually less hydrophilic than their parent compounds (typically amines), the function of NAT appears to be primarily the inactivation of biologically active, potentially toxic compounds, rather than a conversion to more hydrophilic metabolites.1 The role of NATs in the detoxification of the procarcinogenic aryl amines is ambivalent but dependent on the nature of the substrate N-acetylation of the aromatic amine is a detoxification reaction, since it competes with the formation of the hydroxylamine, i.e., with the initiation of the toxification pathway. However, if N-oxidation takes place first, the resulting hydroxylamine is also a substrate for NAT leading to the N-O-acetate ester (an acetoxyamino-group) from which acetate is easily cleaved off, which results in the generation of a reactive nitrenium ion. Thus, the balance between toxification and detoxification...

Use in Prevention and Therapy

Vitamin C plays a central role in anti-oxidant and immune defenses against cancer. It helps detoxify carcinogenic food additives (such as nitrates, pesticides, and other chemicals) and heavy metals. Vitamin C may reduce risk of cancer, particularly cancers of the mouth, larynx, esophagus, stomach, rectum, bladder, breast, pancreas, and uterus.3 Heavy metal toxicity. Vitamin C plays an important role in protecting the body from heavy metals. It reduces absorption and speeds up detoxification and excretion of heavy metals.

Activity of metabolites

Historically, the selection of the large toxicological species using the in vitro interspecies comparison study performed with liver microsomes or hepatocytes was the major link between metabolism studies and safety (see 5.39 Computational Models to Predict Toxicity). Today, with the early identification of human metabolites, the question of their potential positive (pharmacological) or negative (toxicological) activity can be asked (see 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs).

Toxic Optic Neuropathies Definition

Ethambutol and other antitubercular drugs, cytostatic agents, heavy metals, hexachlorophene, and methanol can all cause a toxic optic neuropathy (also see Chap. 17). The first priority is to identify the offending agent and then to block further exposure. Specific measures that follow are determined by the nature of the toxin. The most common syndrome of toxic damage to the optic nerve chiasm is that of tobacco-alcohol amblyopia. It is thought that the toxin in question is cyanide, which is present in trace quantities in tobacco smoke. Interventional therapy with oral multivitamins (e.g., vitamin B complex) and intramuscular injections of hydroxycobalamine (the decyanated form of vitamin B12) can reverse the visual loss in the early stages of the disease. These vitamins are thought to chelate trace levels of cyanide and detoxify the affected tissues. Some individuals may be more at risk than others are, based on the composition of their mitochondrial DNA and variations in the...

Consequences of Altered Glucose Metabolism Oxidative Stress

Reactive oxygen species, if not detoxified by the antioxidant systems, exert a toxic action on polyunsaturated fatty acids, circulating proteins, proteins of cell surface, enzymes and nucleic acid (DNA), leading to irreversible damage of cell structure and functions. Thus, an adequate presence and functioning of antioxidant systems is paramount for cell activity. In advanced cancer patients the high levels of ROS are caused by 2. An inadequate detoxification due to altered glucose metabolism in addition to symptoms such as anorexia cachexia, nausea, and vomiting, that prevent a normal nutrition and thereby a normal supply of nutrients such as glucose, proteins and vitamins, leading to accumulation of ROS 53 . In a series of our recently published studies

Cardiovascular System

Transient hypertension is noted in nearly 50 of alcoholics undergoing detoxification and is related to quantity of drinking and severity of other withdrawal symptoms. Epidemiological studies have demonstrated that alcohol elevates blood pressure independently of age, body weight, or cigarette smoking (Klatsky, Friedman, & Armstrong, 1986). A 10-year follow-up study found even moderate intake of alcohol (< 23 grams day) significantly increased the risk for hypertension in men, independent of age and body mass index. The risk of hypertension was increased for women, but not significantly, when age and body mass index were controlled (Ohmori et al., 2002).

Cysteine and Glutathione

Antioxidant and detoxification function. Cysteine, alone or as part of glutathione, is a potent antioxidant, protecting against free radical damage.2 Glutathione, working with the enzyme glutathione peroxidase (a selenium-containing enzyme), detoxifies free radicals, drugs, and toxic chemicals. It also recycles oxidized vitamin E and vitamin C, conserving body stores of these antioxidants.3

Recommended Daily Intakes

Recommended doses for L-cysteine are in the range of 500-1500 mg day. If the primary aim of therapy is increasing glutathione levels, cysteine should be supplemented with glu-tamine and selenium. Selenium supports optimum functioning of the glutathione detoxification system5. The glutathione that is oxidized during detoxification reactions is reconverted to active glutathione by enzymes requiring vitamin B2 (riboflavin) and vitamin B12. Thus, riboflavin

The requirement for the MER database

A small collection of SWISS-PROT and EMBL entries are taken from the Mer Operon, a bacterial gene cluster that is found in many bacteria for the detoxification of Mercury Hg2+ ions. These provide the raw data to a database, which is called MER. The MER database contains four tables

Treatment And Management Of Substance Use Disorders

The initial phase of addiction treatment is usually concerned with providing safe and humane detoxification from the substance of abuse. Benzodiazepines are recommended as the treatment of choice in management of alcohol or sedative hypnotic withdrawal (Mayo-Smith, 1997), although some clinicians have also advocated the use of anticonvulsants (Pages and Ries, 1998 Malcolm et al., 2001). Detoxification can generally be done at the same dosages as those for seronegative patients until the later stages of HIV illness, when lower doses may be necessary. Methadone detoxification is the preferred method of managing opioid withdrawal. Schedules using bu-prenorphine and or clonidine for opioid detoxification are also available (NIH Consensus Development Conference, 1998). Detoxification from cocaine and stimulants is not done pharmacologically. After medical stabilization and detoxification, the goals of treatment should include maintenance of abstinence when possible and rapid treatment of...

Applications in Substance Abuse Research

Using such techniques, investigations haven fallen broadly into two areas as relates to substance abuse, including both the acute effects of drug administration and the long-term consequences of addiction on neuronal activity (e.g., during states of drug abstinence and or treatment). Among the first to exploit such techniques for studies of human drug abusers, London and colleagues (London et al., 1990) examined the effects of intravenous cocaine (30 mg) on rCGM using 18F FDG and PET. Cocaine induced global reductions in brain metabolism that were inversely correlated with ventricular size. These investigators posited that reductions in brain metabolism may be one mechanism whereby drugs are reinforcing rewarding. In addition, Volkow and colleagues have attempted to understand the metabolic correlates of both acute (i.e., < 1 wk) and sustained (i.e., 1-4 mo) drug abstinence in chronic cocaine abusers (Volkow et al., 1991, 1993). The latter studies have indicated patterns of...

Psychosocial Treatments

L., Bigelow, G. E., Liebson, I. A., Jasinski, D. R., & Johnson, R. E. (1988). A clinical trial of buprenorphine Comparison with methadone in the detoxification of heroin addicts. Clin Pharmacol Ther, 43, 72-78. Cheskin, L. J., Fudala, P. J., & Johnson, R. E. (1994). A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids. Drug Alcohol Depend, 36, 115-121. Hensel, M., & Kox, W. J. (2000). Safety, efficacy, and long-term results of a modified version of rapid opiate detoxification under general anesthesia A prospective study in methadone, heroin, codeine, and morphine addicts. Acta Anaesthsiol Scand, 44(3), 326-333. Kleber, H. D., Riordan, C. E., Rounsaville, B., Kosten, T., Charney, D., Gaspari, J., et al. (1985). Clonidine in outpatient detoxification from methadone maintenance. Arch Gen Psychiatry, 42, 391-394. O'Connor, P. G., Waugh, M. E., Carroll, K. M., Rounsaville, B. J., Diagkogiannis, I. A., &...

Why Do We Need to Detect Sulfur

Sulfur is assimilated and used by several organisms in different ways. As a characteristic part of enzymes and structure proteins, it plays an important part in, for example, biological redox systems, blood coagulation, and the natural detoxification of many organisms and is essential for their development. On the other hand, many organic sulfur compounds such as thiols, sulfides, and disulfides are a risk to human health and the environment.

Gene Environment Interactions

Another way in which inherited susceptibility to cancer may be expressed is the way in which an individual can handle carcinogenic insults from the environment. For example, some individuals have a reduced capacity to metabolize carcinogens such as arylamines because of a slow acetylator phenotype, related to polymorphisms in the N-acetyltransferase-2 gene. Others may have a decreased ability to detoxify a number of carcinogenic agents due to polymorphisms in the glutathione S-transferase gene GSTM-1 or cytochrome P-450 genes CYP2A6 or CYP2D6. Genes that regulate metabolism of drugs and other xenobiotics are often discussed under the heading of pharmacogenetics. A number of genetic polymorphisms that are related to human pharmacogenetic disorders are listed in Table 3 11. Evidence from a study of monozyotic

Toxicogenomics Evolution Of The Field

Most toxicogenomics studies to date have involved hepatotoxicants 23,36, 38-44,47,49,50,52-55,57,59,60,204 , as the liver is the primary source of xenobiotic metabolism and detoxification and because liver injury is the principal reason for withdrawal of new drugs from the market 205 . Toxicogenomics studies have also addressed nephrotoxicity 44,45,51 , neurotoxicity 206,207 , reproductive toxicity 48 , as well as lung toxicity 39,56 , skin toxicity 208 , and cardio toxicity 209 . Expression profiles are altered by experimental conditions, including the harvest method, the in vitro culture method, and the vehicle used to deliver an agent, time of day of sacrifice, and diet. Up to 9 of the transcripts in mouse liver fluctuated with circadian cycling 216 . These included genes controlling glucose metabolism and vesicle trafficking or cytoskeleton, as might be anticipated from changes in the diet of animals during the day and night. In addition transcript levels of Cyp17 and Cyp2a4,...

Traditional Views Of The Cp

Lying within the central ventricular system, the CP is in an ideally suited position to monitor and modulate the functional status of the brain. The CP protects the brain against acute neurotoxic insults by using a complex, mul-tilayered detoxification system. First, the CP contains high concentrations of glutathione (GSH), cysteine, and metallothioneins that potently sequester toxic agents. Second, the CP uses protective enzymes, e.g., superoxide dismutase, GSH-S-transferase, and GSH peroxidase and reductase, to provide a barrier against free-radical oxidative stress. Third, the CP aids in the overall biodistribution of drugs and toxic compounds by using a full compliment of metabolizing enzymes, including phase I enzymes used for the functionalization of such drugs as cytochrome P-450 (CYP) isoform CYP2B1,2 and monoamine oxidase, phase II enzymes used for the conjugation of drugs (e.g., UDP-glucuronosyl transferase), and phase III activity, which provides kidney-like transport...

Organochlorine Compounds Polycyclic Aromatic Hydrocarbons and Breast Cancer

Was not a dose-dependent relationship between exposure and adduct formation, suggesting that there is a threshold effect. This latter point is interesting because there are known polymorphisms in the enzymes that activate and detoxify PAHs, thus a pharmacogenetic analysis could reveal who may be at higher risk.

Modulating metabolism

Focusing upon phase 2 metabolic events, two pathways take on prominence, i.e., when such functionality is present, these particular events have a high likelihood of occurring. These two pathways are also depicted in Figure 15 and, in perfect accord with 'drug metabolism's rule of one' can again almost always be counted on to be highly susceptible to steric hindrance. The glutathione detoxification pathway is also a rapid phase 2 biotransformation reaction but since it

Buprenorphine Subutex

Buprenorphine is an opioid with mixed agonist-antagonist properties that may be abused or used as an alternative to methadone in detoxification from opiates (21). It is taken sublingually, and self-administration of the drug in the custodial environment must be personally supervised by the doctor who should observe the patient for 5 min to ensure that the drug has fully dissolved (22). An unusual property of buprenorphine is that after chronic administration the onset of the abstinence syndrome is delayed. Heroin addicts who are dependent on a small dose of opiate can be transferred onto buprenorphine, which can be withdrawn fairly easily because of the delayed onset of the abstinence

Cognitive Behavioral and Nonpharmacological Treatments

Tity is considered unimportant, patients are less likely to manifest overt resistance. Rather than emphasize powerlessness, this approach assumes that people have within themselves the capacity to change. Although the efficacy of MET MI for cocaine abusers has yet to be proven, it would appear that its unique focus on readiness should, at minimum, help patients to engage in other forms of therapy. In addition, a few studies have begun to support the use of MET MI for treatment of cocaine abuse and dependence. In a small study examining 27 female workers with concurrent cocaine or heroin dependence, MI significantly reduced the women's cocaine use (Yahne, Miller, Irvin-Vitela, & Tonigan, 2002). Similarly, compared to patients who only underwent a detoxification program, patients who also received MI were more likely to be abstinent from cocaine following detoxification and demonstrated higher abstinence rates throughout the following relapse prevention treatment. In addition, MI was...

Effects of Selenium Deficiency on Gene Expression

Cells grown or maintained in selenium deficient media do not become spontaneously malignant, they still require a carcinogenic stimulus, which may be chemical, physical, viral or genetic. However, an insufficient supply of selenium evidently results in adaptive changes facilitating the malignant transformation of cells. The extent of these changes has recently been elucidated through a study (39) with cells from the intestine of mice. When these cells were grown under conditions of selenium deficiency, as many as 44 of their genes were up-regulated, among them genes associated with DNA repair and the protection against oxidative stress and genes controlling cell cycle. In addition, at least 24 genes were down-regulated, those involved with selenoprotein synthesis, the synthesis of enzymes involved in detoxification (cytochrome P450, GSH S-transferase, epoxide hy-drolase) as well as the synthesis of enzymes regulating lipid transport, angiogenesis, cell adhesion, cell cycle, and cell...

Delayed Manifestations

CNS neurotoxicity predominates Confined to basal ganglia globus pallidus, putamen, hippocampus (CT confirmation) resulting in toxic parkinsonism, with bradykinesia, dystonia, dysarthria, no rigidity (L-dopa resistant). Chronic low-level cyanide toxicity occurs in (1) Tobacco amblyopia (male smokers) (2) tropical (cassava root) ataxic neuropathy, (3) Leber's hereditary optic atrophy (males). Mechanism low endogenous stores of CN-detoxify-ing hydroxocobalamin and thiosulfate. Results from depletion of detoxifying substances by chronic low-grade CN poisoning from cigarette smoking (tobacco amblyopia and Leber's heredity optic atrophy) or frequent cassava root ingestion (tropical ataxic neuropathy).

The Putative Role of the Thioredoxin Reductases

In addition to GSH-Px, thioredoxin reductases (TRxRs) (42) deserve particular attention, whose primary function is to catalyze the reduction of the oxidized forms of thioredoxins back into their reduced forms. Thioredoxins are ubiquitous low molecular weight proteins containing two Cys-SH groups in their active reduced forms and a di-sulfide (Cys-S-S-Cys)-linkage in their oxidized forms. Thioredoxins serve as electron donors in a multitude of biologically important reactions, such as DNA synthesis, DNA repair, gene transcription, cell growth, apoptosis, detoxification reactions, including those involving carcinogens, and they in addition help to maintain the functioning of the immune system. The TRxRs have surprisingly low substrate specificity. In addition to the thioredoxins they also reduce protein disulfide isomerase, selenite, selenodiglutathione, nitrosoglutathione, glutathione peroxidase, H2O2, and lipid hydroperoxide reductase, alloxan, and vitamin K, NK lysine disulfide,...

Modeling of Phase 2 Metabolism Enzymes

GSTs catalyze the nucleophilic attack of the thiol of the tripeptide glutathione (GSH) on electrophilic substrates, a reaction usually resulting in addition or substitution, depending on the nature of the substrate.68 Many diverse compounds, including toxic xenobiotics and reactive products of intracellular processes such as lipid oxidation, act as GST substrates.69 The primary function of GST isoenzymes is generally considered to be detoxification of both endogenous and xenobiotic compounds.70,71 However, GSTs can also lead to the formation of more reactive intermediates, either directly or following conversion of glutathione conjugates by other biotransformation enzymes. In some cases the glutathione conjugates formed are labile, and dissociate to the parent electrophile in other tissues.71 Substrates for GSTs share three common features they are hydrophobic, contain an electrophilic atom, and also react nonenzymatically with GSH.68 Sulfate conjugation generally produces a highly...

Metabolism of Alcohol

Once absorbed, alcohol is eliminated at a fairly constant rate, with 90 being metabolized in the liver and the remainder excreted unchanged in urine, breath, and sweat. The rate of elimination in moderate drinkers may vary between 10 and 20 mg 100 mL blood h, with a mean of 15 mg 100 mL blood h. Chronic alcoholics undergoing detoxification have elimination rates of 19 mg 100 mL blood h or even higher (17). This increased rate of alcohol burnoff is believed to be a consequence of increased activity of hepatic microsomal enzymes (P450IIE).

Federal Regulations For Prescribing A Scheduled Controlled Substance

However, one must keep good records to document that the clinician is treating a pain syndrome, not the disease of narcotic addiction (opioid maintenance or detoxification). If the clinician is going to administer or dispense directly (but not prescribe), a Schedule II narcotic drug to a narcotic-dependent person for detoxification or maintenance treatment, the clinician must have a separate registration with the DEA as a NTP (21 CFR 1306.07). DEA does not impose any limitations on a physician or authorized hospital staff to administer or dispense but not prescribe narcotic drugs in a hospital to maintain or detoxify a narcotic-dependent person as an incidental adjunct to medical or surgical treatment of conditions other than addiction (21 CFR 1306.07).

Environmental Transformations and Toxicity

PAHs require metabolic activation to produce their mutagenic or carcinogenic effects. The primary mechanism of PAH biotransformation in higher organisms is by cytochrome P450-based monooxygenases leading to detoxification and excretion. However, attack by cytochrome P4501A1 can activate certain PAHs such as B a P to form a mutagenic diol epoxide capable of forming DNA adducts. The carcinogenesis of nitro-PAHs involves ring oxidation and nitro-reduction to form Af-hydroxyamino-PAH intermediates that can bind with DNA. The formation of hydroxy-PAH metabolites allows PAHs to be excreted by higher organisms. PAHs can bioconcentrate or bioaccumulate in aquatic invertebrates such as molluscs that do not posses the ability for their biotransformation while fish can effectively biotransform PAHs, preventing biomagnification up the food chain.23

Cns Targets For Hiv Infection

Astrocyte function, critical for the survival of neurons, may be impaired in the context of HIV-1 infection. Astrocytes are responsible for maintaining homeosta-sis in the CNS and are important in the detoxification of excess excitatory amino acids such as extracellular glutamate levels (Wesselingh and Thompson, 2001 Deshpande et al., 2005). However, infected astrocytes can produce cellular factors that may adversely affect neuronal survival (Lawrence and Major, 2002). Astrocytes play a dual role in the pathogenesis of HIV-related encephalopathy. In HIV-1 infection, astrocyte glutamate reuptake is impaired, possibly due to interactions with infected macrophages (Fine et al., 1996 Jiang et al., 2001). In addition, glutamate release from the astrocyte is induced by activated macrophages (Vesce et al., 1997 Bezzi et al., 2001). Activation of the CXCR4 receptor by stromal cell-derived factor 1 (SDF-1) results in the release of extracellular TNF-a and downstream release of glu

Application Of Mri To Study Metabolic Disorders

Spectroscopy investigations are performed to study brain chemistry and ascertain from the individual 1H visible chemicals some of the following information with regard to disease NAA for its role in mitochondrial oxidative metabolism and as a putative marker for neuronal viability as well as its role in lipid synthesis (source of acetyl groups) creatine and phospho-creatine as creatine to phosphocreatine energy conversion mediated is by creatine kinase choline, a precursor for neu-rotransmitter acetylcholine and membrane phospholipids, phosphatidylcholine, and sphingomyelin myo-inositol, neuronal signaling of the phosphoinositide pathway, osmoregula-tion, cell nutrition, and detoxification lactate, which is a byproduct of anaerobic metabolism, elevated concentrations resulting from glycolytic metabolism as happens in brain ischemia and glutamate and glutamine, which are major excitatory and inhibitory neurotransmitters in the central nervous system (CNS refs. 6 and 7).

Quantitative Sar Qsar analysis in the safety assessment of constituents

Relatively small differences in substructural features may have a dramatic effect on the metabolism of the constituent or the analog, or even alter the reactivity of the molecules with DNA (genotoxic versus nongenotoxic), thus changing the detoxification pathway or the molecule's mode of action. For example, metabolic activation of N-nitrosamines to potential carcinogenic metabolites is thought to proceed through hydroxylation at the carbon alpha to the nitroso group. Hydroxylation is followed by the release of the hydroxyalkyl moiety as an aldehyde and the generation of a primary nitrosamine (Klaassen, 2001). The primary amine ultimately forms a carbonium ion that can interact with DNA. Therefore, the use of nitrosamines containing aliphatic chains (see Fig. 7.1) may not be suitable analogs for N-nitrosodiphenylamine (see Fig. 7.2) since Fig. 7.2 does not contain a carbon alpha to the nitroso group that can undergo hydroxylation thus altering the metabolic detoxification pathway for...

Micronutrients Alcohol

Alcohol can cause widespread cell damage and fat peroxidation in the liver.8 Supplements may help protect against oxidative damage. Vitamin C may help detoxify alcohol9 Deficiency is very common in heavy drinkers and can produce heart and neuromuscular problems The main enzymes that detoxify alcohol are dependent on zinc, thus zinc deficiency impairs abilityto breakdown alcohol, increasing potential

Treatment Considerations

In the acute setting, multiple SUDs present the treatment team with significant challenges. Given a patient's complicated history of recent and chronic use of multiple substances, the clinician in the emergency room or detoxification unit often struggles to make treatment priorities out of a constellation of signs and symptoms that may be the result of intoxication or withdrawal from a number of substances. Given the frequent occurrence of multiple substance use diagnoses (particularly between alcohol and other drugs), any attempt to attribute observed findings associated with comorbid substance use to a single substance, or class of substances, is often difficult, if not impossible. Intoxication from stimulants may result in psychotic symptoms, but so does withdrawal from sedatives. Lethargy is not only a classic sign of opioid intoxication but also a consequence of stimulant withdrawal. A patient who currently uses both benzo-diazepines and crystal methamphetamine, and presents with...

Discontinuation of Benzodiazepine

Discontinuation of sedatives and hypnotics, including the benzodiazepines, can be divided into three categories (1) long-term low-dose benzodiazepine use, (2) high-dose benzodiazepine abuse and multiple drug abuse, and (3) high-dose abuse of nonbenzodiazepine sedatives and hypnotics (especially intermediate-acting barbiturates). The first group of patients can usually be discontinued on an outpatient basis. Some of the second and even the third group can be treated as outpatients, but most will require inpatient care. Inpatient discontinuation today with managed care is generally reserved for patients who fail at outpatient discontinuation and for those who demonstrate acutely life-threatening loss of control over their drug use. The pharmacological management of inpatient benzodiazepine withdrawal from nontherapeutically high doses of these medicines is covered in standard texts dealing with inpatient detoxification (Wesson et al., 2003).

Epoxide hydrolases EC 3323

Epoxide hydrolases (EHs)38 catalyze the hydrolytic cleavage of oxirane rings. Because of the higher electron attracting force of the oxygen atom compared with the two carbon atoms of oxirane rings, epoxides possess two electrophilic carbon atoms, the electrophilic reactivity of which is enhanced by the tension of the three-membered oxirane ring. Depending on the influences of the rest of the molecule this can make epoxides highly cytotoxic, genotoxic, and carcinogenic. Therefore, the EH-catalyzed hydrolytic opening of oxirane rings is normally a detoxification reaction. Some important, and predictable, exceptions are discussed below. aspartate to form an enzyme-substrate ester that is hydrolyzed by a water molecule activated by proton abstraction through the histidine acidic amino acid pair. This releases the product, a vicinal (trans-, if applicable) diol, and restores free enzyme. While the second step of detoxification (hydrolysis of the enzyme-substrate ester to give the diol...

Pharmacological Interventions And Treatment Implications

Naltrexone is used to help patients avoid relapse after they have been detoxified from opioid dependence. Its main therapeutic action is to occupy mu opioid receptors in the brain with a 100-fold higher affinity than agonists such as methadone or heroin, so that addictive opioids cannot link up with them and stimulate the brain's reward system. Naltrexone does not activate the G-protein-coupled cyclic AMP system and does not increase or decrease levels of cyclic AMP inside the neuron, and it does not promote these brain processes that produce feelings of pleasure (Kosten & Kleber, 1984). An individual who is adequately dosed with naltrexone does not obtain any pleasure from addictive opioids and is less motivated to use them. An interesting neurobiological effect of naltrexone is that it appears to increase the number of available mu opiate receptors, which may help to renormalize the imbalance between the receptors and G-protein coupling to cyclic AMP (Kosten, 1990). Naltrexone is...

The Challenges of Predicting Toxicity

The metabolic fate of a chemical, or the susceptibility of a compound to undergo biological transformations, can have a profound effect on its ability to cause toxicity. Often a drug compound itself can be benign, but can be metabolized to a reactive intermediate that can elicit a toxic response following exposure to the drug. In other instances, metabolism can lead to detoxification of a drug molecule. Kalgutkar et al.5 provide an extensive review of typical substructures that have been shown to be metabolized to reactive intermediates and have been associated with the expression of adverse drug reactions (ADRs). The problem occurs when the body runs out of glutathione. As glutathione stores are diminished, NAPQI is not detoxified, and covalently binds to the lipid bilayer of hepatocytes, causing centrilobular necrosis, resulting in hepatotoxicity. The maximum daily dose of paracetamol is 4 g in adults and 90 mgkg _ 1 in children. A single ingestion

Metabolism

Drug metabolism is the phase of biochemical transformation of the drug. It is highly variable among drugs and depends on biological conditions. The metabolism phase is absent for the few drugs that are not transformed. As explained in great detail in other chapters (see 5.05 Principles of Drug Metabolism 1 Redox Reactions 5.06 Principles of Drug Metabolism 2 Hydrolysis and Conjugation Reactions 5.07 Principles of Drug Metabolism 3 Enzymes and Tissues 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs 5.09 Immuno-toxicology 5.10 In Vitro Studies of Drug Metabolism 5.33 Comprehensive Expert Systems to Predict Drug Metabolism 5.43 Metabonomics), biotransformations may involve one or more successive reactions From a physicochemical point of view, drug metabolism is expected to yield metabolites of lower lipophilicity relative to the parent drug, e.g., by adding an ionizable group. As a result, metabolites are often excreted faster than the parent...

Cooh

As their name implies, small organic anions (300-500 Da) possess a net negative charge at physiological pH and their transepithelial transport into the negatively charged environment of the cell requires energy. This is largely to the OATs (SLC22 family) that are found mainly in cells playing a critical role in the excretion and detoxification of xenobiotics. The OAT family contains six members (OAT1, OAT2, OAT3, OAT4, OAT5, and URAT1), present mainly in the liver, kidney, placenta, brain capillaries, and choroid plexus (Table 4). Their topological structures are very similar to those of the OCTs (Figure 6), but they have more complex energy requirements.94 The members of the OAT1, OAT2, and OAT3 group form a tertiary active system, with the first driving element being a Na + gradient furnished by the Na +, The OAT proteins play a critical role in the excretion and detoxification of a wide variety of drugs, toxins, hormones, and neurotransmitter metabolites. Uremic toxins, which...

Overview

In terms of their xenobiotic function, the drug-metabolizing enzymes can create or unmask hydrophilic moieties in such xenobiotics in order to facilitate their renal clearance (e.g., cytochrome P450 (P450), flavin-containing monooxygenase (FMO), esterases, glucuronyltransferases, sulfotransferases), or they can detoxify electrophilic species that may be damaging to the cell (e.g., epoxide hydrolase, carbonyl reductases and glutathione (GSH) transferases). This enzymatic division is not a strict one, as certain oxidative P450 reactions and conjugation reactions, for example, can be viewed as bioactivation processes that convert a relatively benign compound into a more reactive species.2 Regardless, these diverse proteins can be divided operationally into three main categories (1) redox enzymes, that catalyze oxidation and reduction reactions (2) hydrolases, that catalyze reaction of water with esters, amides, and epoxides and (3) transferases, that conjugate xenobiotics with relatively...

Emotion

For psychopathological symptoms to dissipate in conjunction with abstinence from alcohol and drugs following the initial period of detoxification and withdrawal. Furthermore, it is essential to recognize that emotional distress can both precipitate and sustain a psychopathological disorder. Characterizing the client's emotional status therefore enables the clinician to determine the relation of psychopathology to substance abuse either as a predisposing condition, a correlate of the disorder, or a consequence of the disorder.

Other hydrolases

Glutathione (GSH) and glutathione S-transferases (GSTs)48 represent the prime defense system against elec-trophile-mediated drug toxicity in mammals However, as is the case with all adequately investigated drug-metabolizing enzymes, GSTs in some predictable cases act as toxifying enzymes and glutathione is itself mutagenic when activated by rat kidney homogenates (S9).49 The 'normal' detoxifying role of GSTs is due to the fact that they detoxify lipophilic and structurally very diverse electrophiles by conjugating them with the endogenous hydrophilic nucleophile glutathione. This neutralizes the electrophilic reactivity and renders the compound easily excretable.1 Glutathione conjugates are released from the cells by an active transport system that belongs to the multidrug resistance (MDR) protein complex. Since the GSTs are often strongly product-inhibited this active removal of the products is important for the efficiency of GST-mediated detoxification.50 Nucleophilic addition of...

Species Differences

It is important to choose the appropriate animal species for the analysis of the metabolism of a drug, in order to make predictions for metabolism-dependent toxicities in man. An impressive example of wrong predictions concerning toxification versus detoxification was the use of cynomolgus monkeys as an animal species closely related to man in the assessment of the carcinogenicity of heterocyclic amines present in cooked meat. Cynomolgus monkeys do not possess the heterocyclic amine toxifying CYP1A2. Thus, the study gave false-negative results. In contrast, these heterocyclic amines were potent carcinogens in the marmoset, a primate with a significant level of CYP1A2.

Treatment Method

Colon therapy is claimed to be beneficial because it involves detoxification. It is believed that waste material on the walls of the intestine is toxic and that this material is absorbed into the bloodstream and produces disease. This toxic material is removed through colonic irrigation, and beneficial effects are allegedly produced.

Induction

Induction has been defined as an increased level of enzyme gene expression (see 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs), and hence an increase in enzyme activity, resulting from exposure to a xenobiotic or endogenous components.87

Endocrine System

Thyroid dysfunction is common in alcoholics. Consistent findings indicate reduced thyroxine, and total and free triodothyronine concentrations in early abstinence. A blunted thyroid stimulation test is found in one-third of alcoholics during detoxification and into the early weeks of abstinence. A direct toxic effect of alcohol on the thyroid is likely, which in turn induces a compensatory activation of the hypothalamic-pituitary (HP) axis (Hermann, Heinz, & Mann, 2002).

Biochemical Reactor

A wide range of antibiotics, vitamins, amino acids, fine chemicals, and foodstuffs are manufactured biochemically. Detoxification of industrial and domestic waste water is also carried by biochemical means. The heart of a biochemical process is the reactor. In a bioreactor, the transformation of raw materials into desired products is carried out by the enzyme systems, living microorganisms or by isolated enzymes. The reaction products are formed by three basic processes, namely

Background

Multidrug-resistance associated protein (MRP) is also a member of the ABC superfamily and is capable of efflux and intracellular sequestration in conjunction with glutathione conjugation or cotransport (26,28). MRP describes a group of transporters, of which MRP1 is the only member implicated in drug transport. The substrate specificity of MRP1 is similar but more limited than Pgp, and its normal physiologic role may be detoxification of intracellular oxi-dants. It has been suggested that the location of MRP1 genes on chromosome 16 may contribute to the favorable prognosis found in patients with AML with inv(16) abnormalities. MRP1 is typically assessed using flow cytometry. Functional assays using fluorescent dyes in the presence or absence of reversers, such as cyclosporine and probenecid (26), or after glutathione depletion (11), can specifically assess MRP-mediated efflux.

Withdrawal

The opioid withdrawal syndrome can easily be suppressed by administering any opioid with significant same-receptor agonism as the drug that originally produced the addiction. However, it is more useful to prevent opioid withdrawal symptoms pharmacologically with a nonaddicting drug. This approach furthers the goals of detoxification and abstinence. When circumstances force addicts to treat their withdrawal symptoms without opioids, they most commonly use alcohol and or benzodiazepines. The main disadvantage to this approach is that because of the lack of cross-tolerance between opioids and alcohol benzo-diazepines, blockade of withdrawal symptoms requires the ingestion of large amounts of these sedatives to achieve suppression. Clonidine, a presynaptic alpha2 agonist originally marketed as an antihypertensive, represents an effective and safer alternative for the treatment of opiate withdrawal symptoms (Koob & Bloom, 1988 O'Connor et al., 1995). It can partially suppress many (but...

Maintenance

After detoxification, relapse prevention must be actively addressed with whatever treatment interventions are available. Unfortunately, a large percentage of addicts seem unable to tolerate acute withdrawal, to succeed at controlled detoxification, or to remain drug free. Methadone maintenance may then become the treatment of choice. Administered on a once-a-day schedule, methadone in appropriate doses blocks opioid withdrawal, thus reducing compulsive drug-seeking behavior and use. The individual may then focus energy and attention on more productive behaviors. Indications for the use of methadone maintenance include (1) a history of chronic, high-dose opioid abuse (2) repeated failures at abstinence (3) history of prior successful methadone maintenance (4) history of drug-related criminal convictions or incarcerations (5) pregnancy, especially first and third trimesters and (6) HIV seropositivity. Some individuals report that heavy labor with much perspiration reduces the...

Integration Of Data

Despite the numerous successes of toxicogenomics in the context of toxicology, a poorly addressed but confounding issue pertinent to drug safety and human risk assessment is the impact of the individual genetic background on the response of the individual animal or human patient. The PharmGKB pharmacogenetics knowledgebase 143 cataloges the different human genetic backgrounds by their susceptibility to drug therapy. In addition the NIEHS Environmental Genome Project (EGP 24 ) is identifying SNPs in genes that are important in environmental disease, detoxification, and repair. Linkages of toxicogenomics knowledgebases with those containing information about SNPs and human susceptibility will gradually lead to a more complete picture of the relevance of the responses and genotypes of surrogate animal species to human risk assessment.

Bn80927

Tafluposide (F11872) (33) is a novel phosphate prodrug of a lipophilic, perfluorinated epipodophyllotoxin, and is an example where significant modification of a topo II inhibitor has altered its spectrum of enzyme activity. Tafluposide has superior antitumor activity in vivo compared to etoposide.176 Although it does not inhibit the religation step of the catalytic cycle of either topo I or topo II, it is a potent inhibitor of the catalytic activities of both enzymes. It does not bind to DNA, but inhibits the binding of the enzymes to DNA in a drug- and enzyme-dependent manner177 and possibly represents a new class of topoisomerase agent. A resistant P388 leukemia subline retained marked collateral sensitivity to cisplatin, topotecan, colchicine, and Vinca alkaloids, with no overexpression of resistance-related proteins or modification of the glutathione-mediated detoxification process. However, nucleotide excision repair activity was decreased threefold, suggesting that both...

Polymorphism

Modifying MM risks in different individuals. The human xenobiotic metabolizing system is responsible for completing the detoxification of procarcinogens. The system comprises two classes of enzymes phase 1 cytochrome P450 and phase 2 enzymes, including glutathione S-transferases (GST Ml and GST T1), paraoxonase 1 (PON1), and N-acetyltransferases (NAT) 1 and 2. Interindividual variability in the xeno-biotic enzyme system can predispose certain racial groups to the carcinogenic effects of certain chemicals. In a case-control study using peripheral blood or bone marrow biopsy specimens from 90 Caucasian individuals and a control group consisting of 205 healthy Caucasian volunteer bone marrow donors, there was a significant increase in incidences of the GST T1 null PON1 BB and NAT2 slow acetylation genotypes in MM cases compared with controls. Multivariate analysis revealed that GST T1 null was the most significant risk factor for MM. Interestingly the GST T1 enzyme has been identified as...

Taurine

Taurine is classified as a conditionally essential amino acid because it is an amino acid that the body needs and is unable to synthesize on its own, yet it is not used for proteins. Taurine functions as a free amino acid or simple peptide and plays an important role in mammalian development. Taurine is involved in several different metabolic processes including detoxification, cell membrane stabilization, and the regulation of cellular calcium levels (26). These are all important metabolic processes involved in the maintenance and function of neuronal activity. How critical a role taurine plays in these processes remains uncertain. In the brain, taurine is an inhibitory neurotransmitter. It appears that a genetic variation in taurine metabolism is present in some cases of epilepsy (27). It has not proven to be very effective as a preventive antiepileptic agent because only a small fraction of taurine in the blood system will cross the blood-brain barrier. Increased levels of taurine...

Vision

General Morphology of the Eye Superficially, cephalopod eyes are astoundingly similar to those of marine vertebrates (Pumphrey, 1961 Levine, 1980 Messenger, 1981 for detailed reviews, see Messenger, 1981, 1991 Budelmann et al., 1997). They are fluid filled, with well-defined retina, lens, and pupil. Their transparent lens crys-tallins are derived by recruiting detoxification stress proteins such as glutathione S-transferase (Tomarev et al., 1991). In cephalopods, the lens is suspended by ciliary muscles and interrupted by a connective that partitions the eye into anterior and posterior chambers. There is almost no spherical aberration in the lens, and its very short focal length conforms to the Matthiessen ratio of 2.5 times the lens radius, as it does in fishes. This allows a depth of focus from a few centimeters to infinity (Pumphrey, 1961 Muntz, 1977a Sivak, 1991 Sivak et al., 1994).

Swissmodel

The Mer Operon is a system by which bacteria can detoxify reactive Hg2+ (mercury) ions into metallic mercury (Hg0) using the compound NADPH, nicotinamide adenine dinucleotide phosphate. The system has been well characterised in terms of functionality tests in laboratory experiments, mutagenesis experiments and the features of the DNA protein sequences for many different organisms. The proteins of the Mer Operon are one of the major detoxification mechanisms in mercury-contaminated soils, which often occurs as the result of human activities, especially gold mining. It is also the principal resistance mechanism bacteria possess against the mercurial compounds that were used in some of the first antibiotics, even though it is now somewhat dubious how effective many of these treatments were in the first place.

Modern Well Being

The universe, derived from both eastern Asian and Western classical-vitalist cosmologies. It pays close attention to the action of primary elements (earth, air, fire, water, metal, and wood), and to the old existential or environmental categories such as air, food and drink, exercise, sleep and work, the evacuations, and passions of the mind. The body is seen as existing in a biological envelope through which the cosmic physical forces of 'bio-energy' (or ying and yang) flow with a transcendent psychic energy that can be either harmful or benign. There is a particular interest in the tonic therapeutic actions and reactions of the five senses (acting not only through the nose, but through the eyes, the hands, the ears, and the voice) and in psychosomatic medicine generally the term favoured by progressive holistic GPs is 'biopsychosocial medicine'.46 The techniques used to control bio-energy are mainly those preserved and developed in the ancient practical-medicine traditions of...

Diet Alcohol

Further lowers nutrient absorption from foods. The liver is particularly vulnerable to alcohol - more than three drinks a day causes inflammation and accumulation of fat in the liver. This impairs liver function, reducing the ability to detoxify chemicals and drugs. Because the liver is important for blood sugar control, alcohol-induced liver damage can produce hypoglycemia, leading to fatigue, irritability, and concentration difficulties. Alcohol increases urinary losses of many minerals, including zinc, calcium, and magne-sium.5 Because of these effects, a diet rich in fresh fruits and vegetables, whole grains, lean meats, and low-fat milk products should be carefully chosen.

S100a6

Endogenous secreted soluble RAGE (esRAGE) binds to the diverse RAGE ligands. It could therefore participate to the removal and detoxification of the ligands involved in human diseases by acting as a decoy. The potential use of esRAGE as a therapeutic target was investigated in animal models and results of these studies consistently indicated that administration of esRAGE reduced or limited the development of most RAGE-dependent human disorders. Specifically, esRAGE suppressed Alzheimer's disease-associated pathology and reduced the transport of Ap peptide across the blood-brain barrier in an Alzheimer's disease mouse model (Deane et al., 2003 Lue et al., 2001). In addition, injection of esRAGE in mice blocked the development of tumours and metastasis as well as inflammation and prevented diabetes-associated impaired wound healing (Goova et al., 2001 Hofmann et al., 1999 Taguchi et al., 2000). esRAGE also emerged as a disease marker and clinical studies revealed a specific decrease of...