RT Journal Article
SR Electronic
T1 Toxicokinetic interaction between hepatic disposition and pulmonary bioactivation of inhaled naphthalene studied using Cyp2abfgs-null and CYP2A13/2F1-humanized mice with deficient hepatic cytochrome P450 activity
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.088930
DO 10.1124/dmd.119.088930
A1 Nataliia Kovalchuk
A1 Qing-Yu Zhang
A1 Jacklyn Kelty
A1 Laura S Van Winkle
A1 Xinxin Ding
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/10/08/dmd.119.088930.abstract
AB Previous studies using Cyp2abfgs-null (lacking all genes of the Cyp2a, 2b, 2f, 2g, and 2s subfamilies), CYP2A13/2F1-humanized, and liver-Cpr-null (LCN) mice showed that, whereas hepatic P450-enzymes are essential for systemic clearance of inhaled naphthalene, a possible human carcinogen, both hepatic and extrahepatic P450s may contribute to naphthalene-induced lung toxicity via bioactivation. Herein, we aimed to further understand the toxicokinetics of inhaled naphthalene, to provide a basis for predicting the effects of variations in rates of xenobiotic disposition on 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 "Cyp2abfgs-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 following 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 continued increase in plasma naphthalene levels after termination of active inhalation exposure, was accompanied by prolonged bioactivation of naphthalene in the lung. Additionally, transgenic expression of human CYP2A13/2F1 in the respiratory tract caused a reduction in plasma naphthalene levels (by 40%, relative to "Cyp2abfgs-null-and-LCN") 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 accumulation of naphthalene in liver and lung in mice with compromised hepatic P450 activity; ability of tissue-stored naphthalene to redistribute to the circulation after termination of active inhalation exposure, prolonging exposure of target tissues to naphthalene; and 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.