5alpha-reduced C21 steroids are substrates for human cytochrome P450c17.
The 5alpha-reduction of testosterone in target tissues is a key step in androgen physiology; however, 5alpha-reduced C(19) steroids are sometimes synthesized in testis via a pathway that does not involve testosterone as an intermediate. We studied the metabolism of 5alpha-reduced C(21) steroids by human cytochrome P450c17 (hCYP17), the enzyme responsible for conversion of C(21) steroids to C(19) steroids via its 17alpha-hydroxylase and 17,20-lyase activities. hCYP17 17alpha-hydroxylates 5alpha-pregnan-3,20-dione, but little androstanedione is formed by 17,20-lyase activity. hCYP17 also 17alpha-hydroxylates 5alpha-pregnan-3alpha-ol-20-one and the 5alpha-pregnan-3alpha,17alpha-diol-20-one intermediate is rapidly converted to androsterone by 17,20-lyase activity. Furthermore, 5alpha-pregnan-3alpha,17alpha-diol-20-one is a better substrate for the 17,20-lyase reaction than the preferred substrate 17alpha-hydroxypregnenolone and cytochrome b(5) stimulates androsterone formation only 3-fold. Both 5alpha-pregnan-3alpha-ol-20-one and 5alpha-pregnan-3alpha,17alpha-diol-20-one bind to hCYP17 with higher affinity than does progesterone. We conclude that 5alpha-reduced, 3alpha-hydroxy-C(21) steroids are excellent, high-affinity substrates for hCYP17. The brisk metabolism of 5alpha-pregnan-3alpha,17alpha-diol-20-one to androsterone by CYP17 explains how, when 5alpha-reductases are present, the testis can produce C(19) steroids androsterone and androstanediol from 17alpha-hydroxyprogesterone without the intermediacy of androstenedione and testosterone.
Gupta
Manisha K
MK
Division of Endocrinology and Metabolism, Department of Internal Medicine, 5323 Harry Hines Blvd., Dallas, TX 75390-8857, USA.
Guryev
Oleg L
OL
Auchus
Richard J
RJ
D043582:5-alpha-Dihydroprogesterone / Q000737:chemistry* / Q000378:metabolism*; D000728:Androgens / Q000096:biosynthesis*; D006066:Gonads / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D011280:Pregnanolone / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000737:chemistry* / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D000728:Androgens; D011993:Recombinant Fusion Proteins; D013256:Steroids; D043582:5-alpha-Dihydroprogesterone; D011280:Pregnanolone; D013254:Steroid 17-alpha-Hydroxylase