THE ROLE OF CYTOCHROME B(5) IN THE BIOSYNTHESIS OF ANDROGENS BY HUMANP450C17

Human cytochrome b(5) has a profound effect on the 17,20-lyase activit ies catalyzed by purified, human cytochrome P450c17. It enhances the c onversion of 17 alpha-hydroxypregnenolone to dehydroepiandrosterone by 13-fold and the conversion of 17 alpha-hydroxyprogesterone to androst enedione by at least 10-fold. This latter activity is virtually undete ctable in the absence of cytochrome b(5). Other activities catalyzed b y P450c17 include 17 alpha-hydroxylation of progesterone and pregnenol one and are much less influenced by cytochrome b(5). The conversion of pregnenolone to 17 alpha-hydroxypregnenolone is increased by 2-fold, while that of progesterone to 17 alpha-hydroxyprogesterone is unchange d. These studies using purified systems suggest that cytochrome b(5) p lays a role in regulating the activities of P450c17 to optimize the ba lance between sex hormone synthesis and glucocorticoid synthesis. In p articular, they indicate that in human testes which contains a high b( 5)/P450 ratio, 17 alpha-hydraxyprogesterone can serve as an intermedia te in testosterone production, rather than being a dead-end product, o r stated another way, because of the relatively high concentration of cytochrome b(5) in the human testis, both the Delta 4 and the Delta 5 steroidogenic pathways can lead to testosterone production. (C) 1995 A cademic Press, Inc.