Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona (N.K., Q.-Y.Z., X.D.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York (N.K., Q.-Y.Z.); Center for Health and the Environment, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, California (J.K., L.V.W.); and College of Nanoscale Science, State University of New York Polytechnic Institute, Albany, New York (X.D.).
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona (N.K., Q.-Y.Z., X.D.); Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York (N.K., Q.-Y.Z.); Center for Health and the Environment, Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, California (J.K., L.V.W.); and College of Nanoscale Science, State University of New York Polytechnic Institute, Albany, New York (X.D.)
Drug Metab Dispos. 2019 Dec;47(12):1469-1478. doi: 10.1124/dmd.119.088930. Epub 2019 Oct 8.
Previous studies using -null (lacking all genes of the , , , , and subfamilies), CYP2A13/2F1-humanized, and liver--null (LCN) mice showed that although hepatic cytochrome P450 (P450) enzymes are essential for systemic clearance of inhaled naphthalene (a possible human carcinogen), both hepatic and extrahepatic P450 enzymes may contribute to naphthalene-induced lung toxicity via bioactivation. Herein, we aimed to further understand the toxicokinetics of inhaled naphthalene in order to provide a basis for predicting the effects of variations in rates of xenobiotic disposition on the extent of target tissue bioactivation. We assessed the impact of a hepatic deficit in naphthalene metabolism on the toxicokinetics of inhaled naphthalene using newly generated -null-and-LCN and CYP2A13/2F1-humanized-and-LCN mice. We determined plasma, lung, and liver levels of naphthalene and naphthalene-glutathione conjugate, a biomarker of naphthalene bioactivation, over time after naphthalene inhalation. We found that the loss of hepatic naphthalene metabolism severely decreased naphthalene systemic clearance and caused naphthalene to accumulate in the liver and other tissues. Naphthalene release from tissue, as evidenced by the continued increase in plasma naphthalene levels after termination of active inhalation exposure, was accompanied by prolonged bioactivation of naphthalene in the lung. In addition, transgenic expression of human CYP2A13/2F1 in the respiratory tract caused a reduction in plasma naphthalene levels (by 40%, relative to -null-and-LCN mice) and corresponding decreases in naphthalene-glutathione levels in the lung in mice with hepatic P450 deficiency, despite the increase in local naphthalene-bioactivating P450 activity. Thus, the bioavailability of naphthalene in the target tissue has a significant effect on the extent of naphthalene bioactivation in the lung. SIGNIFICANCE STATEMENT: In this study, we report several novel findings related to the toxicokinetics of inhaled naphthalene, the ability of which to cause lung carcinogenesis in humans is a current topic for risk assessment. We show the accumulation of naphthalene in the liver and lung in mice with compromised hepatic cytochrome P450 (P450) activity; the ability of tissue-stored naphthalene to redistribute to the circulation after termination of active inhalation exposure, prolonging exposure of target tissues to naphthalene; and the ability of non-CYP2ABFGS enzymes of the lung to bioactivate naphthalene. These results suggest potentially large effects of deficiencies in hepatic P450 activity on naphthalene tissue burden and bioactivation in human lungs.
先前的研究使用 -null（缺乏 、 、 、 和 亚家族的所有基因）、CYP2A13/2F1 人源化和肝 -null（LCN）小鼠表明，尽管肝细胞色素 P450（P450）酶对于全身清除吸入性萘（一种可能的人类致癌物）是必不可少的，但肝外 P450 酶可能通过生物激活作用导致萘诱导的肺毒性。在此，我们旨在进一步了解吸入性萘的毒代动力学，以便为预测外源化学物质处置率变化对靶组织生物活化程度的影响提供依据。我们评估了肝内萘代谢缺陷对吸入性萘毒代动力学的影响，方法是使用新生成的 -null-and-LCN 和 CYP2A13/2F1 人源化-and-LCN 小鼠。我们测定了吸入萘后不同时间血浆、肺和肝中萘和萘 - 谷胱甘肽缀合物（萘生物活化的生物标志物）的水平。我们发现，肝内萘代谢的丧失严重降低了萘的全身清除率，并导致萘在肝脏和其他组织中积累。组织中萘的释放（证据为主动吸入暴露终止后血浆中萘水平持续升高）伴随着肺中萘的生物活化延长。此外，呼吸道中人 CYP2A13/2F1 的转基因表达导致血浆中萘水平降低（相对于 -null-and-LCN 小鼠降低 40%），并相应降低肝 P450 缺陷小鼠肺中萘 - 谷胱甘肽水平，尽管局部萘生物活化 P450 活性增加。因此，靶组织中萘的生物利用度对肺中萘生物活化的程度有显著影响。意义声明：在这项研究中，我们报告了与吸入性萘毒代动力学相关的几项新发现，萘在人类中引起肺癌的能力是当前风险评估的一个主题。我们显示了肝细胞色素 P450（P450）活性受损的小鼠肝和肺中萘的积累；组织中储存的萘在主动吸入暴露终止后重新分布到循环中，延长了靶组织接触萘的时间；以及肺中非 CYP2ABFGS 酶对萘的生物活化能力。这些结果表明，肝 P450 活性缺陷对人肺中萘的组织负担和生物活化可能产生重大影响。
