Sindhu R K, Rasmussen R E, Yamamoto R, Fujita I, Kikkawa Y
Department of Pathology, College of Medicine, University of California at Irvine 92717, USA.
Toxicol Lett. 1995 Apr;76(3):227-38. doi: 10.1016/0378-4274(95)80007-z.
Six-week-old ferrets were exposed head-only to clean air or environmental tobacco smoke (ETS) for 2 h/day, 5 days a week for a total of 8 weeks. Exposure to ETS caused a significant reduction in the levels of hepatic microsomal cytochrome P450 and P450 reductase activity in both the male and female ferrets. The content of cytochrome b5 and the activity of its reductase were significantly reduced in the hepatic microsomes of female ferrets. 7-Ethoxycoumarin O-deethylase activity and cytochrome P450 (CYP) 1A protein were markedly decreased in the hepatic microsomes of both the male and female ferrets after ETS exposure. In accord with the downregulation of P450, total metabolites formed from benzo[a]pyrene were significantly reduced in the liver homogenates of ETS-exposed animals. Similarly, sum total of free (+)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide, glutathione conjugates and DNA-bound metabolites formed from precursor (-)-7R-trans-benzo[a]pyrene-7,8-dihydrodiol showed marked reduction in both the male and female ferrets after ETS exposure in a dose-response manner. This is the first report showing downregulation of hepatic P450 and accompanying benzo[a]pyrene metabolism after tobacco smoke exposure which apparently occurred after an initial upregulation of these parameters (Rasmussen et al. (1994) FASEB J. 8, A122).
六周龄的雪貂仅头部暴露于清洁空气或环境烟草烟雾（ETS）中，每天2小时，每周5天，共8周。暴露于ETS导致雄性和雌性雪貂肝脏微粒体细胞色素P450水平和P450还原酶活性显著降低。雌性雪貂肝脏微粒体中细胞色素b5的含量及其还原酶的活性显著降低。ETS暴露后，雄性和雌性雪貂肝脏微粒体中的7-乙氧基香豆素O-脱乙基酶活性和细胞色素P450（CYP）1A蛋白均显著降低。与P450的下调一致，ETS暴露动物肝脏匀浆中由苯并[a]芘形成的总代谢产物显著减少。同样，由前体（-）-7R-反式-苯并[a]芘-7,8-二氢二醇形成的游离（+）-反式-苯并[a]芘-7,8-二氢二醇-9,10-环氧化物、谷胱甘肽结合物和DNA结合代谢产物的总和在ETS暴露后，雄性和雌性雪貂中均呈剂量反应性显著降低。这是第一份报告显示烟草烟雾暴露后肝脏P450下调以及伴随的苯并[a]芘代谢变化，而这些参数在最初上调后显然发生了变化（拉斯穆森等人，（1994年）《美国实验生物学会联合会杂志》8卷，A122）。
