Borlakoglu J T, Scott A, Henderson C J, Jenke H J, Wolf C R
University of Reading, Department of Biochemistry and Physiology, UK.
Biochem Pharmacol. 1993 Apr 6;45(7):1373-86. doi: 10.1016/0006-2952(93)90035-u.
At day 15 of gestation, rats were injected with a single i.p. dose of 100, 250 and 500 mg/kg body weight of a mixture of polychlorinated biphenyls (PCBs) (Aroclor 1254). Seven days later, significant increases in maternal and foetal cytochrome P450, cytochrome b5 and cytochrome c (P450) reductase were found. Concomitantly, the metabolism of nitroanisole, aniline, ethoxyresorufin and benzo[a]pyrene was significantly increased, but foetal metabolism of dimethylnitrosamine was not detectable and only marginal increases in the metabolism of aminopyrine and aldrin were seen. In contrast, maternal metabolism of dimethylnitrosamine, aminopyrine and aldrin was measurable, but significant increases were determined only with the latter substrate. Transplacental transfer of PCBs resulted in increased metabolism of substrates catalysed by foetal CYP1A1 and CYP2B1, but there was no evidence for CYP2E1-catalysed reactions. Further measurements show significant increases in foetal and maternal epoxide hydrolase, glutathione-S-transferase and UDP-glucuronyl transferase activities, thus suggesting that treatment with Aroclor 1254 resulted in coordinated increases in foetal and maternal oxidative and post-oxidative drug metabolism. Western blot analysis of microsomal proteins shows the induction of foetal and maternal CYP1A1, CYP1A2, CYP2A1, CYP2B1, CYP3A1 and CYP4A1. In addition, increased expression of CYP2C6 was seen with the mother but not the foetus. Unlike the mother, foetal rats did not express CYP2E1 and the expression of the above-listed P450 isoenzymes was greater in the mother than the foetus. Northern blot analysis shows significant increases in maternal and foetal CYP1A1, CYP1A2 and CYP2B1 mRNA. An increased amount of CYP3A1 mRNA was only seen with the mother, but not the foetus. Treatment of mothers with Aroclor 1254 resulted in reduced CYP2A1, CYP2C7, CYP2E1 and CYP4A1 mRNA. Insignificant differences in the expression of foetal CYP2A1 and CYP4A1 mRNA were found, but in utero exposure to PCBs reduced the amounts of CYP2E1 mRNA and there was no foetal CYP2C7 mRNA transcript. Treatment with Aroclor 1254 increased the expression of the protooncogenes c-Ha-ras and c-raf in the mother and the foetus, but at varying intensities. Pregnancy itself was linked to an increased expression of these protooncogenes. erbA and erbB mRNA was not detected.
在妊娠第15天，给大鼠腹腔注射单剂量100、250和500毫克/千克体重的多氯联苯（PCBs）混合物（Aroclor 1254）。7天后，发现母体和胎儿的细胞色素P450、细胞色素b5和细胞色素c（P450）还原酶显著增加。同时，对硝基苯甲醚、苯胺、乙氧基试卤灵和苯并[a]芘的代谢显著增加，但未检测到胎儿对二甲基亚硝胺的代谢，仅观察到氨基比林和艾氏剂代谢的少量增加。相比之下，母体对二甲基亚硝胺、氨基比林和艾氏剂的代谢是可测量的，但仅在后者底物上有显著增加。PCBs的胎盘转运导致胎儿CYP1A1和CYP2B1催化的底物代谢增加，但没有证据表明存在CYP2E1催化的反应。进一步测量显示胎儿和母体的环氧水解酶、谷胱甘肽-S-转移酶和UDP-葡萄糖醛酸基转移酶活性显著增加，因此表明用Aroclor 1254处理导致胎儿和母体氧化及氧化后药物代谢的协同增加。微粒体蛋白的蛋白质印迹分析显示胎儿和母体的CYP1A1、CYP1A2、CYP2A1、CYP2B1、CYP3A1和CYP4A1被诱导。此外，母亲体内CYP2C6的表达增加，而胎儿未增加。与母亲不同，胎儿大鼠不表达CYP2E1，上述列出的P450同工酶在母亲体内的表达高于胎儿。Northern印迹分析显示母体和胎儿的CYP1A1、CYP1A2和CYP2B1 mRNA显著增加。仅在母亲体内观察到CYP3A1 mRNA量增加，胎儿未增加。用Aroclor 1254处理母亲导致CYP2A1、CYP2C7、CYP2E1和CYP4A1 mRNA减少。胎儿CYP2A1和CYP4A1 mRNA表达无显著差异，但子宫内暴露于PCBs会减少CYP2E1 mRNA量，且未检测到胎儿CYP2C7 mRNA转录本。用Aroclor 1254处理会增加母亲和胎儿中原癌基因c-Ha-ras和c-raf的表达，但强度不同。妊娠本身与这些原癌基因表达增加有关。未检测到erbA和erbB mRNA。
