Babischkin J S, Pepe G J, Albrecht E D
Department of Obstetrics-Gynecology, University of Maryland School of Medicine, Baltimore 21201.
Endocrinology. 1989 Apr;124(4):1638-45. doi: 10.1210/endo-124-4-1638.
We determined whether the reduction in placental progesterone (P4) production observed after administration of the antiestrogen ethamoxytriphetol (MER-25) to pregnant baboons was associated with a decline in activity and/or content of the placental mitochondrial cholesterol side-chain cleavage system (P-450scc). Pregnant baboons (Papio anubis) were untreated (n = 9) or administered MER-25 (25 mg/kg BW, orally; n = 6) daily on days 140-170 of gestation (term = 184 days). Placentas were obtained by cesarean section on day 170 of gestation, and P-450scc activity and cytochrome P-450 content were determined on mitochondria-rich fractions. Administration of MER-25 to pregnant baboons resulted in a 40% reduction (P less than 0.01, by Student's t test) in the mean (+/- SE) peripheral serum P4 concentration (6.3 +/- 0.3 ng/ml) compared to that in untreated (10.4 +/- 0.3 ng/ml) baboons. P-450scc activity, as determined by formation of pregnenolone (P5) and P4 during a 30-min incubation (picomoles per mg protein), was 37% lower (P less than 0.01) in placental mitochondria obtained from MER-25-treated baboons (179.8 +/- 25.0) than in that from untreated (285.4 +/- 13.4) baboons. Mitochondrial cytochrome P-450 content, assessed by spectral analysis, was 28% lower (P less than 0.02) in antiestrogen-treated (46.7 +/- 2.1 pmol/mg protein) than in untreated (64.8 +/- 5.2 pmol/mg protein) baboons. The initial (time zero) free cholesterol content (nanomoles per mg protein) of mitochondrial-rich preparations was not significantly different in antiestrogen-treated (189.3 +/- 13.0) and untreated (225.0 +/- 15.1) animals. Collectively, these results suggest that the decline in placental P4 production observed in baboons in response to MER-25 occurs at least in part as a result of a decrease in cytochrome P-450scc activity. The loss in P-450scc activity appears to be an intramitochondrial event and not a result of depletion of the total mitochondrial cholesterol pool. We propose, therefore, that one mechanism by which estrogen may regulate the production of P4 by the placenta during primate pregnancy is via the maintenance of placental mitochondrial cytochrome P-450, the terminal oxidase of cytochrome P-450scc.
我们研究了给怀孕狒狒注射抗雌激素乙氨氧三苯乙烯（MER - 25）后观察到的胎盘孕酮（P4）产量降低是否与胎盘线粒体胆固醇侧链裂解系统（P - 450scc）的活性和/或含量下降有关。怀孕狒狒（埃及狒狒）在妊娠140 - 170天（足月为184天）期间未接受治疗（n = 9）或每天口服MER - 25（25 mg/kg体重；n = 6）。在妊娠第170天通过剖宫产获取胎盘，并测定富含线粒体的部分中的P - 450scc活性和细胞色素P - 450含量。给怀孕狒狒注射MER - 25后，与未治疗的狒狒（10.4±0.3 ng/ml）相比，外周血清P4平均（±SE）浓度降低了40%（P＜0.01，通过学生t检验）。通过在30分钟孵育期间孕烯醇酮（P5）和P4的形成来测定的P - 450scc活性（每毫克蛋白质皮摩尔数），在从接受MER - 25治疗的狒狒获得的胎盘线粒体中（179.8±25.0）比未治疗的狒狒（285.4±13.4）低37%（P＜0.01）。通过光谱分析评估的线粒体细胞色素P - 450含量，在接受抗雌激素治疗的狒狒（46.7±2.1 pmol/mg蛋白质）中比未治疗的狒狒（64.8±5.2 pmol/mg蛋白质）低28%（P＜0.02）。富含线粒体的制剂的初始（零时）游离胆固醇含量（每毫克蛋白质纳摩尔数）在接受抗雌激素治疗的动物（189.3±13.0）和未治疗的动物（225.0±15.1）中没有显著差异。总体而言，这些结果表明，狒狒中观察到的对MER - 25反应的胎盘P4产量下降至少部分是由于细胞色素P - 450scc活性降低所致。P - 450scc活性的丧失似乎是线粒体内的事件，而不是线粒体总胆固醇池耗竭的结果。因此，我们提出，雌激素在灵长类动物妊娠期间调节胎盘P4产生的一种机制可能是通过维持胎盘线粒体细胞色素P - 450，即细胞色素P - 450scc的末端氧化酶。
