Reactions catalyzed by human P450c17 and pathways to C19 steroids. A, The four principal A/B-ring configurations of active endogenous steroids and their precursors: Δ5, Δ4, 5α, and 5α,3α (structures shown at bottom). Progesterone and 17α-hydroxyprogesterone can be 5α-reduced, and once the A-ring is saturated, these 5α-reduced steroids are substrates for reductive 3αHSDs of the AKR1C family. Human P450c17 17α-hydroxylates all four classes of C21 steroids, but the 17,20-lyase activity is robust only with 17α-hydroxypregnenolone and 17-hydroxyallopregnanolone (5α-pregnane-3α,17α-diol-20-one), the Δ5 and 5α,3α pathways, respectively. Dihydroprogesterone, 17-hydroxydihydroprogesterone, and allopregnanolone are trivial names for 5α-pregnane-3,20-dione, 5α-pregnan-17α-ol-3,20-dione, and 5α-pregnan-3α-ol-20-one, respectively. B, Two pathways to DHT using the different 17,20-lyase activities of human P450c17. In the conventional or Δ5-pathway (left), the 17,20-lyase activity of P450c17 requires cytochrome b5 to efficiently convert 17α-hydroxypregnenolone to DHEA, and testosterone is reduced in target tissues by 5α-reductase 2 (5αR2) to DHT. In the “backdoor” or 5α,3α-pathway (right), 5α-reduction by 5αR1 and 3α-reduction of C21 steroids occurs in the steroidogenic tissue before the 17,20-lyase reaction. In the best characterized pathway based on the tammar wallaby pouch young, 17-hydroxyallopregnanolone is cleaved to androsterone without requiring cytochrome b5 and reduced to androstanediol. Androstanediol is exported from the testis and metabolized to DHT by the oxidative 3αHSD activity of 17βHSD6. DHT may also be formed from androsterone via a parallel pathway catalyzed by 17βHSD6 and 17βHSD3, with androstanedione as the intermediate. Note that testosterone is not an intermediate in the backdoor pathway to DHT, that different isoforms of 5α-reductase appear to be involved in the two pathways, and that both reductive and oxidative 3αHSD activities are required for the backdoor pathway. Structures of testosterone, DHT, and androstanediol are shown at bottom. [© R. J. Auchus.]