TY - JOUR
T1 - Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene
AU - Kovalchuk, Nataliia
AU - Kelty, Jacklyn
AU - Li, Lei
AU - Hartog, Matthew
AU - Zhang, Qing Yu
AU - Edwards, Patricia
AU - Van Winkle, Laura
AU - Ding, Xinxin
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/8/15
Y1 - 2017/8/15
N2 - 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 10 ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10 ppm. 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 20 h 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 significant, although relatively small, contribution to airway toxicity of inhaled NA. This hepatic contribution to the airway toxicity of inhaled NA may be an important risk factor for individuals with diminished bioactivation activity in the lung.
AB - 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 10 ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10 ppm. 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 20 h 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 significant, although relatively small, contribution to airway toxicity of inhaled NA. This hepatic contribution to the airway toxicity of inhaled NA may be an important risk factor for individuals with diminished bioactivation activity in the lung.
KW - Airway
KW - Inhalation
KW - Liver
KW - Lung
KW - Metabolism
KW - Naphthalene
KW - P450
KW - Toxicity
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U2 - 10.1016/j.taap.2017.05.015
DO - 10.1016/j.taap.2017.05.015
M3 - Article
C2 - 28527914
AN - SCOPUS:85019944946
SN - 0041-008X
VL - 329
SP - 1
EP - 8
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
ER -