Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice

DOI Web Site Web Site PubMed 37 References
  • Oda Shingo
    Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine
  • Miyazaki Nanaka
    Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine
  • Tsuneyama Koichi
    Department of Molecular and Environmental Pathology, Institute of Health Biosciences, Tokushima University Graduate School
  • Yokoi Tsuyoshi
    Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine

Search this article

Description

<p>Gefitinib (GEF) is the first selective tyrosine kinase inhibitor of epidermal growth factor receptor. It is associated with the occurrence of clinical drug-induced liver injury. Although GEF is metabolized to chemically reactive metabolites by cytochrome P450 3A and 1A enzymes and then conjugated to glutathione (GSH), whether these reactive metabolites contribute to GEF-induced toxicity remains unknown. In this study, we investigated whether GSH depletion can sensitize mice to liver injury caused by GEF. Male C57BL/6J mice were intraperitoneally pretreated with L-buthionine (S,R)-sulfoximine (BSO) at 700 mg/kg to inhibit GSH synthesis and then orally administered GEF at 500 mg/kg every 24 hr for 4 consecutive days. The coadministration of BSO and GEF increased plasma alanine aminotransferase (ALT) levels to approximately 700 U/L and 1600 U/L at 72 and 96 hr after the first administration, respectively, whereas the increase in plasma ALT levels in mice receiving GEF at 500 mg/kg alone was limited, suggesting that GSH plays a protective role in GEF-induced liver injury. Histological examination showed nuclear karyorrhexis and sporadic single hepatocyte death in the livers of BSO+GEF coadministered mice. In these mice, the hepatic expression levels of heme oxygenase 1 (Hmox1) and metallothionein 2 (Mt2) mRNA, caspase 3/7 enzymatic activity, and the amounts of 2-thiobarbiuric acid reactive substances were significantly increased, suggesting the presence of oxidative stress, which may be associated with hepatocellular death. Together, these results show that oxidative stress as well as the reactive metabolites of GEF are involved in GEF-induced liver injury in GSH-depleted mice.</p>

Journal

References(37)*help

See more

Related Projects

See more

Keywords

Details 詳細情報について

Report a problem

Back to top