The role of cytochrome b5 in the biosynthesis of androgens by human P450c17.
Human cytochrome b5 has a profound effect on the 17,20-lyase activities catalyzed by purified, human cytochrome P450c17. It enhances the conversion of 17 alpha-hydroxypregnenolone to dehydroepiandrosterone by 13-fold and the conversion of 17 alpha-hydroxyprogesterone to androstenedione by at least 10-fold. This latter activity is virtually undetectable in the absence of cytochrome b5. Other activities catalyzed by P450c17 include 17 alpha-hydroxylation of progesterone and pregnenolone and are much less influenced by cytochrome b5. The conversion of pregnenolone to 17 alpha-hydroxypregnenolone is increased by 2-fold, while that of progesterone to 17 alpha-hydroxyprogesterone is unchanged. These studies using purified systems suggest that cytochrome b5 plays a role in regulating the activities of P450c17 to optimize the balance between sex hormone synthesis and glucocorticoid synthesis. In particular, they indicate that in human testes which contains a high b5/P450 ratio, 17 alpha-hydroxyprogesterone can serve as an intermediate in testosterone production, rather than being a dead-end product, or stated another way, because of the relatively high concentration of cytochrome b5 in the human testis, both the delta 4 and the delta 5 steroidogenic pathways can lead to testosterone production.
Katagiri
M
M
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
Kagawa
N
N
Waterman
M R
MR
D006907:17-alpha-Hydroxypregnenolone / Q000378:metabolism; D019326:17-alpha-Hydroxyprogesterone; D000446:Aldehyde-Lyases / Q000378:metabolism*; D000728:Androgens / Q000096:biosynthesis*; D000735:Androstenedione / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015786:Cytochromes b5 / Q000494:pharmacology*; D003687:Dehydroepiandrosterone / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D006908:Hydroxyprogesterones / Q000378:metabolism; D007700:Kinetics; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase
D000728:Androgens; D006908:Hydroxyprogesterones; D011994:Recombinant Proteins; D006907:17-alpha-Hydroxypregnenolone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D011284:Pregnenolone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases