Xenobiotic metabolism ketone reductases

Aldehyde reductases and ketone reductases are families of enzymes involved in reductive metabolism of both endogenously produced and xenobiotic aldehydes and ketones (1). Aldehyde reductase activity has been detected in cell-free preparations of... 

Various studies regarding the biotransformation of xenobiotic ketones have established that ketone reduction is an important metabolic pathway in mammalian tissue. Because carbonyl compounds are lipophilic and may be retained in tissues, their reduction to the hydrophilic alcohols and subsequent conjugation are critical to their elimination. Although ketone reductases may be closely related to the alcohol dehydrogenases, they have distinctly different properties and use NADPH as the cofactor. The metabolism of xenobiotic ketones to free alcohols or conjugated alcohols has been demonstrated for aromatic, aliphatic, alicyclic, and unsaturated ketones (e.g., naltrexone, naloxone, hydromorphone, and daunorubicin). The carbonyl reductases are distinguished by the stereospecificity of their alcohol metabolites. 

Carbonyl reduction is a metabolic pathway widely distributed in nature. Many endogenous substances, such as prostaglandins, biogenic amines, and steroids, together with xenobiotic chemicals of several varieties, are transformed to the corresponding alcohols before further metabolism and elimination. Carbonyl reduction in several continuous cell lines was investigated using metyrapone as a substrate ketone. Quercitrin was reported to inhibit carbonyl reductase. 

Bioreduction of ketones often leads to (he creation of an asymmetric center and. thereby, two possible stereoisomeric alcohols. " For example, reduction of acetophenone by a soluble rabbit kidney reductase leads to the enantiomeric alcohols (5)(-)- and (R)( + )-mcthylphen lcarbinol. with the (.V)(-) isomer predominating (3 1 ratio). The preferential formation of one stereoisomer over the other is termed product stereoselectivity in drug metabolism. " Mechanistically, ketone reduction involves a "hydride" transfer from the reduced nicotinamide moiety of the cofactor NADPH or NADH to (he carbonyl carbon atom of the ketone. It is generally agreed that this step proceeds with considerable stereoselectivity." Consequently, it is not surprising to find many reports of xenobiotic ketones that are i uced prefer-emi ly to a predominant stereoisomer. Often, ketone reduction yields dcohol metabolites that arc pharmacologically active. 

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