It is well known that the transformation of T into 5a-DHT by the NADPH-dependent enzyme, 5a-R, has an established physiological role in peripheral androgen-dependent structures, and especially in the control of the development and function of the prostate. The intracellular formation of 5a-DHT precedes the binding of this 5a-reduced steroid to the AR, allowing the receptor-mediated activation of target genes. In the prostate, this metabolic transformation is a mechanism of amplification of the androgenic signal, since 5a-DHT possesses an affinity for the AR about four times higher than that of T (88-91). Moreover, the activated AR appears to be more stable when 5a-DHT is bound (90,91), because this compound exhibits a fivefold slower dissociation rate from the AR than T. 5a-DHT is consequently able to activate transcription at concentrations significantly lower than those of its precursor.
As previously mentioned, all steroids possessing a A4-3keto structure (androgens, PROG, and adrenal steroids) are substrates for the 5a-R, although with different affinities. For both isozymes (see next section), in the rat and in humans, the Kms for the main circulating representatives of the different classes of hormonal steroids rank in the following order: P > T > corticosterone = cortisol.
The reduction of the substrates to their dihydro forms is achieved by the stereospecific hydride transfer from the ^-position of NADPH to the aC5 position of the steroid, yielding the enolate, which is then protonated by the medium, giving the saturated 3-ketone (92,93). The 5a-reduction of the A ring is an irreversible process, and allows the subsequent 3a- or 3^-reduction of the 3-oxo group by the 3a-HOR or 3^-HOR; whereas the 3a-hydroxylation may give active steroids, the 3^-hydroxylation brings to the formation of inactive compounds (28). In general, the reduction of the 3 position decreases the binding affinity to the intracellular receptors. In cooperation with other enzymes (see section "Other Steroid Metabolizing Enzymes"), the 5a-R/3a-HOR system may then participate in the catabolism of high concentrations of potentially neurotoxic steroids (e.g., the glucocorticosteroids, which may induce apoptotic processes on selected neuronal populations of the hippocampus). However, some 5a-reduced-3a-hydroxysteroids may exert important biological effects different from those of the parent steroids (see section "General Consideration on the 3a-HOR). The process of 5a-reduction in itself may play an important role for protecting the brain and several other structures (e.g., the blood vessels) from the damaging effects of an excess of estrogens (94-96), this by utilizing and consequently eliminating the substrates (T and DIONE) of the P450aro. (See refs. 97 and 98 for further details.)
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