[Physiological, genetic and pathological factors regulating the reductive metabolism of drugs with a ketone group]

Abstract

In this review, we describe the physiological, genetic and pathological factors regulating the reductive metabolism of drugs with a ketone group. Acetohexamide (AH) was chosen as a model drug with a ketone group. Species differences of AH reductase activity were observed in liver cytosol and microsomes of animals tested. AH reductase activity in liver microsomes of rats was much higher in males than females. The activity was not detectable until 4 weeks of age after birth in both sexes, but increased markedly at puberty only in males. AH reductase activity in liver microsomes of male rats was decreased by testectomy, and restored by the treatment with testosterone propionate, indicating that the sex-related difference and postnatal development of the activity are regulated by androgens. There was a strain difference of AH reductase activity in liver microsomes of male rats. Of rat strains tested, only Wistar-Imamichi strain was found to lack male-specific microsomal enzyme activity. The inheritance pattern of AH reductase activity in liver microsomes of rats was determined by mating the genetic deficiency Wistar-Imamichi strain with Fischer-344 strain. Streptozotocin-induced diabetes significantly decreased AH reductase activity in liver microsomes of male rats. Furthermore, the physiological role of AH reductase present in liver microsomes of male rats was examined. We propose the possibility that the male-specific microsomal enzyme physiologically functions as a 20 beta-hydroxysteroid dehydrogenase.