5a-Reductase isoenzymes

Males with deficiency of the 5a-reductase isoenzyme do not develop acne, male pattern baldness, or enlarged prostates.274 The last fact was some of the impetus for development of the steroid 5a-reductase inhibitor finasteride, which is widely used to treat benign prostate enlargement 274/277/278 It is an enzyme-activated inhibitor in which the NADH reduces the C= C bond in the A ring, which is not in the same position as in the substrate. The resulting anion cannot become protonated but instead adds to the NAD+ as shown in Eq. 22-15. 

Finasteride and dutasteride are both mechanism-based inhibitors of type 1 and type 2 5a-reductase isoenzymes that inactivate 5a-reductase by an apparent irreversible modification of 5o-reductase (105,106). The inhibition constants (median inhibitory concentrations [ICsos]) in Table 45.5 suggest that finasteride is 30 times more selective for type 2 5a-reductase, whereas dutasteride appears to be approximately 10 times more potent as an inhibitor of type 2 5a-reductase than as a inhibitor of type 1 5a-reductase. The reduction of finasteride to dihydrofinasteride proceeds through an enzyme-bound, NADP-dihydrofinasteride adduct (see Chapter 5) (105). The mechanism- based inhibition explains the exceptional potency and specificity of finasteride and dutasteride in the treatment of BPH. This concept of mechanism-based inhibition may have application to the development of other inhibitors of pyridine nucleotide-linked enzymes. 

Similar to finasteride, dutasteride is a competitive and mechanism-based inhibitor not only of type 2 but also of type 1 5a-reductase isoenzymes, with which stable enzyme-NADP adduct complexes are formed, inhibiting the conversion of testosterone to DHT (106). The suppression of both type 1 and type 2 isoforms results in greater and more consistent reduction of plasma DHT than that observed for finasteride (107,108,109). The more effective dual inhibition of type 1 and type 2 5a-reductase isoforms lowers circulating DHT to a greater extent than with finasteride and shows advantages in treating BPH and other disease states (e.g., prostate cancer) that are DHT-dependent. 

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