Increased susceptibility of Nrf2-Null Mice to 1-bromopropane-induced hepatotoxicity

Fang Liu, Sahoko Ichihara, William M. Valentine, Ken Itoh, Masayuki Yamamoto, Sahabudeen Sheik Mohideen, Junzoh Kitohk, Gaku Ichihara

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36 Citations (Scopus)

Abstract

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-B-Pinduced 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.

Original languageEnglish
Pages (from-to)596-606
Number of pages11
JournalToxicological Sciences
Volume115
Issue number2
DOIs
Publication statusPublished - 2010 Mar 8

Keywords

  • 1-bromopropane
  • Hepatotoxicity.
  • Nuclear factor erythroid 2-related factor 2
  • Oxidative stress

ASJC Scopus subject areas

  • Toxicology

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  • Cite this

    Liu, F., Ichihara, S., Valentine, W. M., Itoh, K., Yamamoto, M., Mohideen, S. S., Kitohk, J., & Ichihara, G. (2010). Increased susceptibility of Nrf2-Null Mice to 1-bromopropane-induced hepatotoxicity. Toxicological Sciences, 115(2), 596-606. https://doi.org/10.1093/toxsci/kfq075