The carbonyl moiety of aldehydes, ketones, and quinones, often encountered in xenobiotic molecules, is the most common target of reductase enzymes, resulting in the formation of hydrophilic alcohols and hydroquinones that can readily undergo conjugation prior to excretion. This is an important biological function in that it provides a protective mechanism against a host of potentially reactive compounds that are formed intracellularly. Carbonyl-reducing enzymes belong to four main categories: (1) the short-chain dehydrogenase/reductase (SDR, EC 1.1.1) superfamily; (2) the AKR (EC 220.127.116.11) superfamily; (3) the ADH (EC 18.104.22.168) family; or (4) the nicotinamide quinone oxidoreductases (NQO1 and NQO2, EC 22.214.171.124).73 These enzymes are all principally cytosolic and NADPH-dependent. Few recombinant forms of these enzymes are widely available, greatly complicating efforts to distinguish between the host of carbonyl-reducing enzymes in the cell for metabolism of a given xenobiotic. However, consideration of enzyme localization, cofactor preference, optimal reaction pH, and chemical inhibitor sensitivity, as outlined in a recent review,73 provide a basis for distinguishing between the major enzyme classes that contribute to carbonyl reduction of xenobiotics.
5.07.2.6.1.1 Short-chain dehydrogenase/reductase superfamily
SDRs are enzymes of great functional diversity found throughout nature. In humans, cytosolic carbonyl reductase (CBR1) is a major member of the SDR superfamily that metabolizes a wide variety of xenobiotics, including the anticoagulant warfarin, anthracycline derivatives like daunorubicin, and aldehyde and ketone products of lipid peroxidation.74 A recent mouse knockout study demonstrated a critical role for CBR1 in the doxorubicin cardiotoxicity that is attributed to the reduced metabolite, doxorubicinol.75 CBR3 is a second member of the cytosolic human carbonyl reductases, but its substrate specificity is not well documented. The major human microsomal carbonyl reductase, 11^-hydroxysteroid dehydrogenase, also belongs to the SDR family. Each enzyme demonstrates a cofactor preference for NADPH, transferring the pro-S hydrogen to the substrate, i.e., the opposite of ADH.
The AKRs perform oxidoreduction on a wide variety of natural and foreign substrates. A systematic nomenclature for the AKR superfamily similar to the P450 nomenclature has been adopted.76,135 The superfamily contains several hundred proteins expressed in prokaryotes and eukaryotes that are distributed over 14 families (AKR1-AKR14). The AKR1 family contains aldehyde reductases (AKR1A), aldose reductases (AKR1B), dihydrodiol dehydrogenases, and 3a, 17b and 20a hydroxysteroid dehydrogenases (AKR1C) and keto steroid 5^-reductases (AKR1D). Another family of drug metabolism interest is AKR7, the aflatoxin aldehyde reductases.77 Crystal structures of many AKRs and their complexes with ligands are available.78 Each structure has the characteristic (a/b) 8-barrel motif of the superfamily, a conserved cofactor binding site, and a catalytic tetrad comprised of conserved Tyr, Asp, His, and Lys residues.
Two forms of cystosolic quinone oxidoreductase have been described. NQO1 (also known as DT-diaphorase) and NQO2 are FAD-containing enzymes that utilize NAD(P)H and dihydronicotinamide riboside, respectively, as electron donors.79 From a functional standpoint, NQO1 has been more extensively studied, and is known to act as a chemoprotective enzyme cellular defenses against the electrophilic and oxidizing metabolites of a wide variety of xenobiotic quinones.80 Obligatory two-electron reduction by the enzyme bypasses the formation of semiquinone radicals, which is important because the semiquinone radical can be reoxidized by molecular oxygen 'futile cycling' with concomitant production of ROS that can lead to cellular damage. NQO1 also participates in reduction of endogenous quinones, such as vitamin E quinone and ubiquinone, generating antioxidant forms of these molecules. Because NQO1 is overexpressed in some tumour types, its enzyme activity has been exploited in the design of anticancer drugs that require reductive bioactivation.81
Intestinal microflora present in the largely anerobic environment of the lower gastrointestinal tract are well known to exhibit nitroreductase and azoreductase activities. In terms of specific reductase enzymes, P450 reductase (CPR, EC 126.96.36.199) is a 76kDa membrane-bound flavoprotein, best recognized in the drug metabolism arena for its role as a coenzyme in P450-dependent oxidative reactions. There the enzyme's role is to transfer electrons, one at a time via its FAD and flavin mononucleotide (FMN) cofactors, from NADPH to P450. However, CPR can also directly reduce a variety of xenobiotics, notably quinones, by one-electron reduction. Under conditions of low oxygen tension, and depending on the redox potential of the ligands, substrates other than molecular oxygen can compete for ferrous cytochrome P450. Notable substrates for the reductive activity of P450 are halogenated hydrocarbons which can undergo reductive dehalogenation. P450-dependent reductive dehalogenation of carbon tetrachloride yielding a trichloroacyl radical that can react with molecular oxygen and initiate lipid peroxidation may be involved in the hepatoxicity of this solvent.
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