Characterization of the 5 alpha-reductase-3 alpha-hydroxysteroid dehydrogenase complex in the human brain

Although androgen metabolism in the human brain was discovered almost 30 yr ago, conclusive studies on the enzymes involved are still lacking. We ther efore investigated 5 alpha -reductase and colocalized 3 alpha -hydroxystero id dehydrogenase (3 alpha -HSD) activity in cerebral neocortex (CX) and sub cortical white matter (SC) specimens neurosurgically removed from 44 patien ts suffering from epilepsy. We could demonstrate the presence of the 5 alph a -reductase-3 alpha -HSD complex in the biopsies of all patients under inv estigation. Inhibition experiments with specific inhibitors for 5 alpha -re ductase type 1 and type 2 revealed strong evidence for the exclusive activi ty of the type 1 isoform. We detected a significantly higher 5 alpha -reduc tase activity in CX than in SC (P < 0.0001), but no sex-specific difference s were observed. Furthermore, we found that, in contrast to liver, only 3<a lpha>-HSD type 2 messenger RNA is expressed in the brain and that its expre ssion is significantly higher in SC than in CX without sex-specific differe nces. The present study is the first to systematically characterize the 5 a lpha -reductase-3 alpha -HSD complex in the human brain. The lack of sex-sp ecific differences and also the colocalization of both enzymes at all life stages suggest a more general purpose of the complex, e.g, the synthesis of neuroactive steroids or the catabolism of neurotoxic steroids, rather than control of reproductive functions.