Paakki P, Stockmann H, Kantola M, Wagner P, Lauper U, Huch R, Elovaara E, Kirkinen P, Pasanen M
Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Environ Health Perspect. 2000 Feb;108(2):141-5. doi: 10.1289/ehp.00108141.
We evaluated the impact of maternal drug abuse at term on human placental cytochrome P450 (CYP)-mediated (Phase I) xenobiotic and steroid-metabolizing activities [aromatase, 7-ethoxyresorufin O-deethylase (EROD), 7-ethoxycoumarin O-deethylase (ECOD), pyrene 1-hydroxylase (P1OH), and testosterone hydroxylase], and androstenedione-forming isomerase, NADPH quinone oxidoreductase (Phase II), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) activities in vitro. Overall, the formation of androstenedione, P1OH, and testosterone hydroxylase was statistically significant between control and drug-abusing subjects; we observed no significant differences in any other of the phase I and II activities. In placentas from drug-abusing mothers, we found significant correlations between ECOD and P1OH activities (p < 0. 001), but not between ECOD and aromatase or P1OH and EROD activities; we also found significant correlations between blood cotinine and UGT activities (p < 0.01). In contrast, in controls (mothers who did not abuse drugs but did smoke cigarettes), the P1OH activity correlated with ECOD, EROD (p < 0.001), and testosterone hydroxylase (p < 0.001) activities. Our results (wider variation in ECOD activity among tissue from drug-abusing mothers and the significant correlation between P1OH and ECOD activities, but not with aromatase or EROD activities) indicate that maternal drug abuse results in an additive effect in enhancing placental xenobiotic metabolizing enzymes when the mother also smokes cigarettes; this may be due to enhancing a "silent" CYP form, or a new placental CYP form may be activated. The change in the steroid metabolism profile in vitro suggests that maternal drug abuse may alter normal hormonal homeostasis during pregnancy.
我们评估了足月时母体药物滥用对人胎盘细胞色素P450（CYP）介导的（I相）外源性物质和类固醇代谢活性[芳香化酶、7-乙氧基异吩恶唑酮O-脱乙基酶（EROD）、7-乙氧基香豆素O-脱乙基酶（ECOD）、芘1-羟化酶（P1OH）和睾酮羟化酶]以及雄烯二酮形成异构酶、NADPH醌氧化还原酶（II相）、UDP-葡萄糖醛酸基转移酶（UGT）和谷胱甘肽S-转移酶（GST）体外活性的影响。总体而言，对照和药物滥用受试者之间雄烯二酮、P1OH和睾酮羟化酶的形成具有统计学意义；我们在任何其他I相和II相活性中均未观察到显著差异。在药物滥用母亲的胎盘中，我们发现ECOD和P1OH活性之间存在显著相关性（p < 0.001），但ECOD与芳香化酶或P1OH与EROD活性之间不存在显著相关性；我们还发现血中可替宁与UGT活性之间存在显著相关性（p < 0.01）。相比之下，在对照组（不滥用药物但吸烟的母亲）中，P1OH活性与ECOD、EROD（p < 0.001）和睾酮羟化酶（p < 0.001）活性相关。我们的结果（药物滥用母亲组织中ECOD活性变化更大，且P1OH与ECOD活性之间存在显著相关性，但与芳香化酶或EROD活性无关）表明，当母亲也吸烟时，母体药物滥用会在增强胎盘外源性物质代谢酶方面产生累加效应；这可能是由于增强了一种“沉默”的CYP形式，或者可能激活了一种新的胎盘CYP形式。体外类固醇代谢谱的变化表明，母体药物滥用可能会改变孕期正常的激素稳态。
