5α-Reductase Isozymes in the Central Nervous System

The enzyme 5α-reductase (5α-R) activates several Δ4–3keto steroids to more potent derivatives which may also acquire new biological actions. Testosterone gives rise to the most potent natural androgen dihydrotestosterone (DHT), and progesterone to dihydroprogesterone (DHP), a precursor of the endogenous anxiolytic/anesthetic steroid tetrahydroprogesterone (THP). Two isoforms of 5α-R, with a limited degree of homology, different biochemical properties and distinct tissue distribution have been cloned: 5α-R type 1 and type 2. In androgen-dependent structures DHT is almost exclusively formed by 5α-R type 2; 5α-R type 1 is widely distributed in the body, with the highest levels in the liver, and may be involved in steroid catabolism. In the brain, the roles of the two isozymes are still largely unknown. This brief review will summarize recent experimental data from our laboratory which try to assign possible functional roles to the process of 5α-reduction, and to the two 5α-R isoforms in the CNS.