Roberts A E, Ritz M A, Hoekstra S, Descotes G, Hincks J R
Sanofi Research Division, Malvern, PA 19355, USA.
J Biochem Toxicol. 1996;11(3):101-10. doi: 10.1002/(SICI)1522-7146(1996)11:3<101::AID-JBT1>3.0.CO;2-O.
The cytochrome P-450 (CYP) mediated hydroxylation of testosterone to 6 beta-, 7 alpha-, and 16 alpha-hydroxytestosterone (b beta-, 7 alpha-, and 16 alpha-OHT) and the dealkylation of ethoxycoumarin to 7-hydroxycoumarin (ECOD) and ethoxyresorufin to resorufin (EROD) were used to probe changes in CYP monooxygenase activities in liver microsomes from rats treated with the androgen receptor antagonist, zanoterone (Z). Phenobarbital (PB) and beta-naphthoflavone (beta-NF) were used as comparators. There were sex-related differences in the constitutive CYP activities and in the responses of CYP activities to Z. The greatest effect of Z administration was on 6 beta-OHT activity: It was increased up to 5.2-fold in males and 13.9-fold in females (Z high dose). The effect was larger than the produced by PB or beta-NF (< or = threefold increases). Z (high dose), PB, and beta-NF increased ECOD to a similar extent, e.g., about 1.3-fold in males and 1.2-2.9-fold in females. beta-NF increased EROD (11.2-fold males, 6.2-fold females) more than PB (3.4- to 4.6-fold) or Z (1.3- to 1.7-fold). Since hydroxylation of testosterone at the 6 beta position in rats and humans is catalyzed primarily by CYP isoforms from the 3A subfamily, the increase in 6 beta-OHT suggests that Z induced CYP 3A activity. These findings were confirmed with Western immunoblots with probes for rat CYP 1A1, 2B1/2, 2E1, 3A, and 4A. Z produced a three-to fourfold increase in the 3A isoform for both male and female rats. Results from this study suggest that in a clinical setting, Z therapy has the potential to induce CYPs of the 3A subfamily and in so doing alter the metabolism and clearance of drugs that are substrates for the 3A subfamily.
细胞色素P-450（CYP）介导的睾酮羟基化为6β-、7α-和16α-羟基睾酮（6β-、7α-和16α-OHT）以及乙氧基香豆素脱烷基化为7-羟基香豆素（ECOD）和乙氧基试卤灵脱烷基化为试卤灵（EROD），被用于探究用雄激素受体拮抗剂扎诺特隆（Z）处理的大鼠肝微粒体中CYP单加氧酶活性的变化。苯巴比妥（PB）和β-萘黄酮（β-NF）用作对照。组成型CYP活性以及CYP活性对Z的反应存在性别相关差异。给予Z的最大作用是对6β-OHT活性：在雄性中增加高达5.2倍，在雌性中增加13.9倍（Z高剂量）。该作用大于PB或β-NF所产生的作用（增加≤3倍）。Z（高剂量）、PB和β-NF使ECOD增加到相似程度，例如，在雄性中约增加1.3倍，在雌性中增加1.2 - 2.9倍。β-NF使EROD增加（雄性中增加11.2倍，雌性中增加6.2倍）比PB（增加至3.4 - 4.6倍）或Z（增加至1.3 - 1.7倍）更多。由于大鼠和人类中睾酮在6β位的羟基化主要由3A亚家族的CYP同工型催化，6β-OHT的增加表明Z诱导了CYP 3A活性。这些发现通过用大鼠CYP 1A1、2B1/2、2E1、3A和4A的探针进行的Western免疫印迹得到证实。Z使雄性和雌性大鼠的3A同工型增加三到四倍。这项研究的结果表明，在临床环境中，Z治疗有可能诱导3A亚家族的CYPs，从而改变作为3A亚家族底物的药物的代谢和清除。
