Human Types 1 and 3 3α-Hydroxysteroid Dehydrogenases: Differential Lability and Tissue Distribution1

3α-Hydroxysteroid dehydrogenases (3α-HSDs) catalyze the conversion of 3-ketosteroids to 3α-hydroxy compounds. The best known 3α-HSD activity is the transformation of the most potent natural androgen, dihydrotestosterone, into 5α-androstan-3α,17β-diol (3α-diol), a compound having much lower activity. Previous reports show that 3α-HSDs are involved in the metabolism of glucocorticoids, progestins, prostaglandins, bile acid precursors, and xenobiotics. 3α-HSDs could, thus, play a crucial role in the control of a series of active steroid levels in target tissues. In the human, type 1 3α-HSD was first identified as human chlordecone reductase. Recently, we have isolated and characterized type 3 3α-HSD that shares 81.7% identity with human type 1 3α-HSD. The transfection of vectors expressing types 1 and 3 3α-HSD in transformed human embryonic kidney (HEK-293) cells indicates that both enzymes efficiently catalyze the transformation of dihydrotestosterone into 3α-diol in intact cells. However, when the cells are broken, the activity of type 3 3α-HSD is rapidly lost, whereas the type 1 3α-HSD activity remains stable. We have previously found that human type 5 17β-HSD which possesses 84% and 86% identity with types 1 and 3 3α-HSD, respectively, is also labile, whereas rodent enzymes such as mouse type 5 17β-HSD and rat 3α-HSD are stable after homogenization of the cells. The variable stability of different enzymatic activities in broken cell preparations renders the comparison of different enzymes difficult. RNA expression analysis indicates that human type 1 3α-HSD is expressed exclusively in the liver, whereas type 3 is more widely expressed and is found in the liver, adrenal, testis, brain, prostate, and HaCaT keratinocytes. Based on enzymatic characteristics and sequence homology, it is suggested that type 1 3α-HSD is an ortholog of rat 3α-HSD while type 3 3α-HSD, which must have diverged recently, seems unique to human and is probably more involved in intracrine activity.