The interrelationship of polycyclic hydrocarbon metabolism and steroidogenesis in primary cultures of bovine adrenal cortical cells.
The interrelationship between adrenal steroidogenesis and polycyclic aromatic hydrocarbon metabolism has been examined in cultured bovine adrenal cortical (BAC) cells. Adrenocorticotropin (ACTH) selectively induced steroidogenic cytochrome P-450-dependent enzyme activities from BAC cell cultures. In the presence of 10(-7) M ACTH, steroid production requiring 17 alpha-hydroxylation (cortisol + androgens) was increased 5-fold over the formation of 17- deoxysteroids (corticosterone). The effect of 10 microns benz[a]anthracene on steroidogenesis was characterized by suppression of both steroid 17 alpha-hydroxylation (90%) and total steroidogenesis (50%), with a concomitant rise in 17- deoxysteroid formation. The order of stimulation of steroidogenic enzyme activities by ACTH (17 alpha-hydroxylase greater than side chain cleavage greater than 21-hydroxylase) paralleled the order of suppression by benz[a]anthracene. BAC cell cultures incubated with Su-10603, a specific 17 alpha-hydroxylase inhibitor, exhibited similar changes in the pattern of steroidogenesis, as did benz[a]anthracene-treated cells, suggesting that benz[a] anthracene also inhibits steroidogenesis as an inhibitor of 17 alpha-hydroxylase. In addition, benz[a]anthracene induced benzo[a]pyrene metabolism 4- to 6-fold over control levels in these cells. The profile of benzo[a]pyrene metabolites revealed predominantly water-soluble products (nonhydrolyzable greater than sulfates greater than glucuronides), 9,10- monooxygenation products, and 3-phenol. ACTH (10(-7) M) and 0.5 mM cyclic AMP each decreased benzo[a]pyrene metabolism by more than 50%. Both benz[a]anthracene-induced and uninduced benzo[a]- pyrene metabolism were equally reduced in response to ACTH and cyclic AMP. In the presence of 0.2 mM aminoglutethimide, which completely inhibited steroidogenesis, ACTH decreased benz[a]anthracene induction of benzo[a]pyrene metabolism to the same extent as ACTH treatment alone. It is concluded that the suppression of benzo[a]pyrene metabolism by ACTH is mediated by cyclic AMP and does not involve steroids generated in response to ACTH. These studies demonstrate that cytochrome P-450 isozymes involved in steroidogenesis and polycyclic aromatic hydrocarbon metabolism are regulated, in opposing directions, by ACTH.
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D001579:Benzopyrene Hydroxylase / Q000096:biosynthesis*; D002417:Cattle; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D011083:Polycyclic Compounds / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D001551:Benz(a)Anthracenes; D011083:Polycyclic Compounds; D013256:Steroids; D013764:Tetrahydronaphthalenes; C001953:SU 10603; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System; C030935:benz(a)anthracene; D006899:Mixed Function Oxygenases; D001579:Benzopyrene Hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases