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

Nataliia Kovalchuk, Jacklyn Kelty, Lei Li, Matthew Hartog, Qing Yu Zhang, Patricia Edwards, Laura Van Winkle, Xinxin Ding

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalToxicology and Applied Pharmacology
Volume329
DOIs
StatePublished - Aug 15 2017

Fingerprint

Biotransformation
Respiratory System
Toxicity
Liver
Lung
Inhalation Exposure
naphthalene
Tissue
Environmental Pollutants
Biomarkers
Metabolites
Nose
Metabolism
Cytochrome P-450 Enzyme System
Glutathione

Keywords

  • Airway
  • Inhalation
  • Liver
  • Lung
  • Metabolism
  • Naphthalene
  • P450
  • Toxicity

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene. / Kovalchuk, Nataliia; Kelty, Jacklyn; Li, Lei; Hartog, Matthew; Zhang, Qing Yu; Edwards, Patricia; Van Winkle, Laura; Ding, Xinxin.

In: Toxicology and Applied Pharmacology, Vol. 329, 15.08.2017, p. 1-8.

Research output: Contribution to journalArticle

Kovalchuk, Nataliia ; Kelty, Jacklyn ; Li, Lei ; Hartog, Matthew ; Zhang, Qing Yu ; Edwards, Patricia ; Van Winkle, Laura ; Ding, Xinxin. / Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene. In: Toxicology and Applied Pharmacology. 2017 ; Vol. 329. pp. 1-8.
@article{3ffa338138764e8985f1a45ec91ef19a,
title = "Impact of hepatic P450-mediated biotransformation on the disposition and respiratory tract toxicity of inhaled naphthalene",
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 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.",
keywords = "Airway, Inhalation, Liver, Lung, Metabolism, Naphthalene, P450, Toxicity",
author = "Nataliia Kovalchuk and Jacklyn Kelty and Lei Li and Matthew Hartog and Zhang, {Qing Yu} and Patricia Edwards and {Van Winkle}, Laura and Xinxin Ding",
year = "2017",
month = "8",
day = "15",
doi = "10.1016/j.taap.2017.05.015",
language = "English (US)",
volume = "329",
pages = "1--8",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",

}

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

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

UR - http://www.scopus.com/inward/record.url?scp=85019944946&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019944946&partnerID=8YFLogxK

U2 - 10.1016/j.taap.2017.05.015

DO - 10.1016/j.taap.2017.05.015

M3 - Article

VL - 329

SP - 1

EP - 8

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

ER -