Ontogenic development

Organ maturation during fetal life and adulthood has a profound effect on the ability of that tissue to metabolize drugs.24,25 Maturation of drug-metabolizing enzymes is perhaps the major factor accounting for age-associated changes in the nonrenal clearance of drugs. Individual variability in drug metabolism during different stages of infancy, childhood, and adolescence can partially be explained by the gradual developement of drug-metabolizing enzymes, and failure to recognize this effect can have important consequences in therapeutics. For example, lack of awareness of the ontogenic regulation of UGTactivity led to the therapeutic disaster in pediatrics known as 'gray-baby' syndrome caused by administration of chloramphenicol, a UGT substrate, to neonates and young infants with an underdeveloped UGT system.26 In these young subjects, chloramphenicol accumulated to toxic concentrations and precipitated cardiovascular collapse. Table 4 contains a list of important hepatic drug-metabolizing enzymes known to be subject to developmental regulation.

In general, P450 expression is low, but detectable, in the developing human fetal liver, increases after birth, and reaches adult levels during the first 10 years of life.27 CYP1A2 is typical in this regard, with fetal hepatic expression of CYP1A2 protein or mRNA essentially absent in samples from individuals in early gestational stages,28'29 but steadily increasing in infants to reach 50% of levels seen in adults at 1 year of age.30 However, temporal expression patterns of individual human liver P450s can vary widely, often among closely related isoforms with the same subfamily. Here the CYP3A family in humans is instructive. Whereas CYP3A4 is the predominant liver isoform in adults, CYP3A7 is the major P450 detected in human embryonic, fetal, and newborn liver. CYP3A7 activity is abundant during embryonic and fetal life and rapidly decreases during the first week of life. In contrast, CYP3A4 levels are very low before birth, but increase steadily thereafter and reach 50% of adulthood levels by 12 months.31 Conversely, CYP3A5 activity and expression levels exhibit large interindividual variability throughout all stages of development and display no obvious developmental pattern.

In humans, the CYP2 subfamily is the most diverse P450 gene family, with the CYP2C and CYP2D subfamilies contributing substantially to xenobiotic metabolism. However, only the ontogenic development of CYP2C9 and CYP2C19 has been investigated in detail.32 CYP2C9 protein levels and catalytic activity in first-trimester human fetal liver reflected only 1-2% of adult values, but increased gradually in later fetal life to reach approximately 30% of adult values. In contrast, CYP2C19 development was much slower, implying that different developmental regulatory mechanisms exist for these two closely related P450 isozymes.

The developmental regulation of P450 enzymes associated with the metabolism of endogenous compounds as well as xenobiotic bioactivation is also of interest. CYP1A1 has been closely associated with the bioactivation of polycyclic aromatic hydrocarbons and other chemical carcinogens. CYP1A1 mRNA levels are detectable in fetal liver, adrenal, and lung, but not the kidney, between 6 and 12 weeks of gestation.33 In all cases mRNA levels decreased with increasing fetal age and were barely detectable in the adult liver, indicating that suppression of CYP1A1 activity occurs some time in the prenatal period, either at birth or during early childhood development.34 CYP2A enzymes have been associated with the metabolism and bioactivation of tobacco-related xenobiotics. None of the human CYP2A enzymes (CYP2A6, CYP2A13, or CYP2A7) were detected in human fetal liver,35 but by 1 year of age, hepatic CYP2A6 concentration was 50% of adult expression levels. In the fetal nasal mucosa, CYP2A6 and CYP2A13, but not CYP2A7, were identified (1-5% of adult expression levels) in fetal tissue samples.36 CYP2J2 has been associated with the epoxidation of endogenous arachidonic acid to biologically active eicosanoids and is abundantly expressed in the adult heart.37,38 This P450 enzyme appears to have a distinctive developmental pattern because CYP2J2 protein levels in fetal liver and olfactory mucosa samples from fetal tissues were comparable to adult levels.36 The impact of ontogeny on P450 enzymes should be taken into account when prescribing drugs, whose clearance highly depends on this pathway, to neonates.

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