Aldo Keto Reductases AKRs

The AKRs are a superfamily of dehydrogenases/reductases.234 Unlike the ADHs, they require NADP+ (H) as a cofactor, and generally catalyze reductive235 rather than oxidative reactions. While they operate on the same kinds of endogenous substrates as the ADHs (e.g., ketosteroids,236 retinal,237 and lipid peroxidation products),238 they also tend to operate on xenobiotics.

At least three AKR isoforms (1C1, 1C2, and 1C4) have been isolated from human liver cytosol that contribute to the reduction of the tobacco-specific carcinogen 4-methynitrosoamino-1-(3-pyridyl)-1-butanone (212) to the less toxic 4-methynitrosoamino-1-(3-pyridyl)-1-butanonol (213), which is susceptible to conjugation and elimination.239

Yanmano et al.240 have isolated and purified two AKRs of the 1C subfamily from rabbit liver cytosol that will reduce the opioid receptor antagonist naloxone (214) to the a- and b-diastereomeric alcohols 215 and 216, respectively (Scheme 26). Interestingly, one AKR, termed NR1, stereospecifically produces 215, while the second, termed NR2, stereospecifically produces 216. Naltrexone (217) and dihydromorphinone (218) were good substrates for NR2 but not NR1. Both enzymes reduced aliphatic and aromatic aldehydes, cyclic and aromatic ketones, and quinones. They also catalyzed the dehydrogenation of 17b-hydroxysteroids with low Km values. The main human AKRs have been cloned and expressed, and their substrate reactivity profiles and tissue and organ distribution determined.241

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