Human carbonyl reduction pathways and a strategy for their study in vitro.
Carbonyl reduction plays a significant role in physiological processes throughout the body. Although much is known about endogenous carbonyl metabolism, much less is known about the roles of carbonyl-reducing enzymes in xenobiotic metabolism. Multiple pathways exist in humans for metabolizing carbonyl moieties of xenobiotics to their corresponding alcohols, readying these molecules for subsequent conjugation and/or excretion. When exploring carbonyl reduction clearance pathways for a drug development candidate, it is possible to assess the relative contributions of these enzymes due to their differences in subcellular locations, cofactor dependence, and inhibitor profiles. In addition, the contributions of these enzymes may be explored by varying incubation conditions, such as pH. Presently, individual isoforms of carbonyl-reducing enzymes are not widely available, either in recombinant or purified form. However, it is possible to study carbonyl reduction clearance pathways from simple experiments with commercially available reagents. This article provides an overview of carbonyl-reducing enzymes, including some kinetic data for substrates and inhibitors. In addition, an experimental strategy for the study of these enzymes in vitro is presented.
Rosemond
M Jane Cox
MJ
Worldwide Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. jane.c.rosemond@gsk.com
Walsh
John S
JS
D000818:Animals; D003600:Cytosol / Q000201:enzymology; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D013379:Substrate Specificity; D015262:Xenobiotics / Q000378:metabolism*
D015262:Xenobiotics; D010088:Oxidoreductases