Milne C M, Hasmall R L, Russell A, Watson S C, Vaughan Z, Middleton M C
Central Toxicology Laboratory, Imperial Chemical Industries PLC, Macclesfield, United Kingdom.
Toxicol Appl Pharmacol. 1987 Sep 30;90(3):427-35. doi: 10.1016/0041-008x(87)90135-9.
Ovulation in the rat is delayed by a single administration of the substituted triazole R151885 (1,1-di(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)-ethanol). This delay results from a 24-hr shift in the preovulatory luteinizing hormone (LH) surge since administration of chorionic gonadotrophin on proestrus restores ovulation. Plasma levels of estradiol are markedly reduced (42-45%) 6-12 hr after administration of R151885. The restoration of ovulation in R151885-pretreated rats, by administration of exogenous estradiol benzoate, indicates that the reduced estradiol levels play a pivotal role in the delay of ovulation. Granulosa cells isolated from rat ovaries produce estradiol and progesterone in vitro in the presence of both follicle-stimulating hormone and testosterone. The addition of R151885 to such cultures results in a dose-dependent inhibition of estradiol production (69% by 1 microM) without a significant effect on progesterone production. This inhibition occurs at concentrations of R151885 similar to those measured in vivo. R151885 is a competitive inhibitor of human placental aromatase (apparent Ki with androstenedione substrate of 410 nM) and produces a type II spectral perturbation of cytochrome P-450 from placental microsomes. Pituitaries isolated from R151885-treated rats have reduced LH output in response to gonadotrophin-releasing hormone stimulation compared with those of controls. It is proposed that R151885 competitively inhibits aromatase activity in developing ovarian follicles. The resultant temporary reduction of plasma estradiol levels at a critical time in the estrous cycle, and consequent inadequate pituitary sensitization, produces a 24-hr delay in the preovulatory LH surge and hence ovulation is delayed by 24 hr.
单次给予取代三唑R151885（1,1 - 二（4 - 氟苯基）-2 -（1,2,4 - 三唑 - 1 - 基）乙醇）会延迟大鼠排卵。这种延迟是由于排卵前促黄体生成素（LH）峰出现24小时的延迟，因为在动情前期给予绒毛膜促性腺激素可恢复排卵。给予R151885后6 - 12小时，血浆雌二醇水平显著降低（42 - 45%）。通过给予外源性苯甲酸雌二醇，可使经R151885预处理的大鼠恢复排卵，这表明雌二醇水平降低在排卵延迟中起关键作用。从大鼠卵巢分离的颗粒细胞在促卵泡激素和睾酮存在的情况下，可在体外产生雌二醇和孕酮。向此类培养物中添加R151885会导致雌二醇生成受到剂量依赖性抑制（1微摩尔时抑制69%），而对孕酮生成无显著影响。这种抑制作用发生时R151885的浓度与体内测得的浓度相似。R151885是人类胎盘芳香化酶的竞争性抑制剂（以雄烯二酮为底物时的表观Ki为410纳摩尔），并会使胎盘微粒体中的细胞色素P - 450产生II型光谱扰动。与对照组相比，从经R151885处理的大鼠分离的垂体对促性腺激素释放激素刺激的LH分泌减少。据推测，R151885竞争性抑制发育中的卵巢卵泡中的芳香化酶活性。在发情周期的关键时期，血浆雌二醇水平随之暂时降低，进而导致垂体致敏不足，使排卵前LH峰延迟24小时，因此排卵延迟24小时。
