Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene

Toxicology and Applied Pharmacology
Nataliia KovalchukXinxin Ding

Abstract

We determined whether a decrease in hepatic microsomal cytochrome P450 activity would impact lung toxicity induced by inhalation exposure to naphthalene (NA), a ubiquitous environmental pollutant. The liver-Cpr-null (LCN) mouse showed decreases in microsomal metabolism of NA in liver, but not lung, compared to wild-type (WT) mouse. Plasma levels of NA and NA-glutathione conjugates (NA-GSH) were both higher in LCN than in WT mice after a 4-h nose-only NA inhalation exposure at 10ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10ppm. Despite the large increase in circulating and lung tissue NA levels, the level of NA-GSH, a biomarker of NA bioactivation, was either not different, or only slightly higher, in lung and liver tissues of LCN mice, relative to that in WT mice. Furthermore, the extent of NA-induced acute airway injury, judging from high-resolution lung histopathology and morphometry at 20h following NA exposure, was not higher, but lower, in LCN than in WT mice. These results, while confirming the ability of extrahepatic organ to bioactivate inhaled NA and mediate NA's lung toxicity, suggest that liver P450-generated NA metabolites also have a significa...Continue Reading

Citations

Apr 26, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Sarah A CarrattLaura S Van Winkle
Sep 26, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Nataliia KovalchukXinxin Ding
Jun 13, 2020·International Journal of Molecular Sciences·Samantha C FaberMichael S Denison
Sep 10, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Nathanial C StevensOliver Fiehn

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