Increased susceptibility of Nrf2-null mice to 1-bromopropane-induced hepatotoxicity.
1-Bromopropane (1-BP) was introduced as an alternative to ozone-depleting solvents. However, it was found to exhibit neurotoxicity, reproductive toxicity, and hepatotoxicity in rodents and neurotoxicity in human. However, the mechanisms underlying the toxicities of 1-BP remain elusive. The present study investigated the role of oxidative stress in 1-BP-induced hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2)-null mice. Groups of 24 male Nrf2-null mice and 24 male wild-type (WT) C57BL/6J mice were each divided into three groups of eight and exposed to 1-BP at 0, 100, or 300 ppm for 8 h/day for 28 days by inhalation. Liver histopathology showed significantly larger area of necrosis in Nrf2-null mice relative to WT mice at the same exposure level. Nrf2-null mice also had greater malondialdehyde (MDA) levels, higher ratio of oxidized glutathione/reduced form of glutathione, and lower total glutathione content. The constitutive level and the increase in ratio per exposure level of glutathione S-transferase (GST) activity were lower in the liver of Nrf2-null mice than WT mice. Exposure to 1-BP at 300 ppm increased the messenger RNA levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GcLm), glutamate-cysteine synthetase (GcLc), glutathione reductase, and NAD(P)H: quinone oxidoreductase 1 (NQO1) in WT mice but not in Nrf2-null mice except for GST Yc2. Nrf2-null mice were more susceptible to 1-BP-induced hepatotoxicity. That oxidative stress plays a role in 1-BP hepatotoxicity is deduced from the low expression levels and activities of antioxidant enzymes and high MDA levels in Nrf2-null mice.
Liu
Fang
F
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Ichihara
Sahoko
S
Valentine
William M
WM
Itoh
Ken
K
Yamamoto
Masayuki
M
Sheik Mohideen
Sahabudeen
S
Kitoh
Junzoh
J
Ichihara
Gaku
G
D000280:Administration, Inhalation; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006842:Hydrocarbons, Brominated / Q000633:toxicity; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D012997:Solvents / Q000633:toxicity*
D004798:Enzymes; D006842:Hydrocarbons, Brominated; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012997:Solvents; C118559:1-bromopropane