Sindhu R K, Rasmussen R E, Kikkawa Y
Department of Pathology, College of Medicine, University of California at Irvine 92717, USA.
J Toxicol Environ Health. 1995 Aug;45(4):453-64. doi: 10.1080/15287399509532008.
To evaluate the effects of "environmental tobacco smoke" (ETS) on developing lungs, juvenile ferrets were exposed to ETS at an average total particulate concentration of 381 +/- 97 mg/m3 for 2 h at the breathing zone. Twenty-four hours after the exposure, the ferrets were sacrificed and the metabolism of (-)-trans-benzo[a]pyrene-7,8-dihydrodiol was studied in the lung and liver homogenates. The rate of conversion of (-)-trans-benzo[a]pyrene-7,8-dihydrodiol to the ultimate carcinogen (+)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10- epoxide was twofold higher in the liver than that observed in the lung of control ferrets. After ETS exposure, the formation of free benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide was increased by 62% in the lung (p < .01). The DNA-bound metabolites were significantly increased only in the lung, while protein-bound metabolites were significantly increased in the liver after ETS exposure. Although glutathione conjugates tended to be increased both in the lung and liver, sulfate conjugates were significantly decreased in the lung after ETS exposure (p < .05). (+)-trans-Benzo[a]pyrene-7,8-dihydrodiol was used to study the relative contributions of cytochrome P-450 and peroxyl radical-mediated formation of benzo[a]-pyrene-7,8-dihydrodiol-9,10-epoxide. Peroxyl radical- and P-450-mediated conversion of (+)-trans-benzo[a]pyrene-7,8-dihydrodiol to benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide was proportionately equal in the ferret lung, whereas in the liver the P-450-mediated pathway was predominant. After ETS exposure there was a tendency for P-450-mediated formation of benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide to increase. These results demonstrate significant differences in the metabolism of (-)-trans-benzo[a]pyrene-7,8-dihydrodiol by the lung and liver of juvenile ferrets and suggest a significant role of peroxyl radical-mediated formation of (+)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide in the lung, which may help explain discrepancy between the levels of P-450 and amounts of DNA adducts of polycyclic aromatic hydrocarbons in different organs in smokers.
为评估“环境烟草烟雾”（ETS）对发育中肺部的影响，将幼年雪貂暴露于呼吸区平均总颗粒浓度为381±97毫克/立方米的ETS中2小时。暴露24小时后，处死雪貂，并在肺和肝匀浆中研究（-）-反式苯并[a]芘-7,8-二氢二醇的代谢。（-）-反式苯并[a]芘-7,8-二氢二醇转化为最终致癌物（+）-反式苯并[a]芘-7,8-二氢二醇-9,10-环氧化物的速率在肝脏中比对照雪貂肺部观察到的速率高两倍。ETS暴露后，肺中游离苯并[a]芘-7,8-二氢二醇-9,10-环氧化物的形成增加了62%（p<.01）。DNA结合代谢物仅在肺中显著增加，而蛋白质结合代谢物在ETS暴露后在肝脏中显著增加。尽管谷胱甘肽结合物在肺和肝脏中均有增加的趋势，但ETS暴露后肺中硫酸盐结合物显著减少（p<.05）。（+）-反式苯并[a]芘-7,8-二氢二醇用于研究细胞色素P-450和过氧自由基介导的苯并[a]芘-7,8-二氢二醇-9,10-环氧化物形成的相对贡献。在雪貂肺中，过氧自由基和P-450介导的（+）-反式苯并[a]芘-7,8-二氢二醇向苯并[a]芘-7,8-二氢二醇-9,10-环氧化物的转化比例相等，而在肝脏中P-450介导的途径占主导。ETS暴露后，P-450介导的苯并[a]芘-7,8-二氢二醇-9,10-环氧化物形成有增加的趋势。这些结果表明幼年雪貂的肺和肝对（-）-反式苯并[a]芘-7,8-二氢二醇的代谢存在显著差异，并表明过氧自由基介导的（+）-反式苯并[a]芘-7,8-二氢二醇-9,10-环氧化物在肺中的形成起重要作用，这可能有助于解释吸烟者不同器官中细胞色素P-450水平与多环芳烃DNA加合物量之间的差异。
