Dibartolomeis M J, Jefcoate C R
Mol Pharmacol. 1984 May;25(3):476-86.
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.
已在培养的牛肾上腺皮质（BAC）细胞中研究了肾上腺类固醇生成与多环芳烃代谢之间的相互关系。促肾上腺皮质激素（ACTH）选择性地诱导BAC细胞培养物中依赖细胞色素P-450的类固醇生成酶活性。在存在10⁻⁷ M ACTH的情况下，需要17α-羟化的类固醇生成（皮质醇+雄激素）比17-脱氧类固醇（皮质酮）的生成增加了5倍。10微米苯并[a]蒽对类固醇生成的影响表现为类固醇17α-羟化（90%）和总类固醇生成（50%）均受到抑制，同时17-脱氧类固醇生成增加。ACTH对类固醇生成酶活性的刺激顺序（17α-羟化酶＞侧链裂解酶＞21-羟化酶）与苯并[a]蒽的抑制顺序平行。用特异性17α-羟化酶抑制剂Su-10603孵育的BAC细胞培养物，其类固醇生成模式的变化与苯并[a]蒽处理的细胞相似，这表明苯并[a]蒽也作为17α-羟化酶的抑制剂抑制类固醇生成。此外，苯并[a]蒽在这些细胞中诱导苯并[a]芘代谢比对照水平高4至6倍。苯并[a]芘代谢产物谱主要显示水溶性产物（不可水解的＞硫酸盐＞葡糖醛酸盐）、9,10-单加氧产物和3-苯酚。ACTH（10⁻⁷ M）和0.5 mM环磷酸腺苷各自使苯并[a]芘代谢降低超过50%。ACTH和环磷酸腺苷对苯并[a]蒽诱导和未诱导的苯并[a]芘代谢的降低程度相同。在存在0.2 mM氨鲁米特（其完全抑制类固醇生成）的情况下，ACTH将苯并[a]蒽对苯并[a]芘代谢的诱导降低到与单独ACTH处理相同的程度。得出的结论是，ACTH对苯并[a]芘代谢的抑制是由环磷酸腺苷介导的，且不涉及对ACTH作出反应而生成的类固醇。这些研究表明，参与类固醇生成和多环芳烃代谢的细胞色素P-450同工酶受ACTH的调节，且调节方向相反。
