title: Involvement of hepatic stellate cell cytoglobin in acute hepatocyte damage through the regulation of CYP2E1-mediated xenobiotic metabolism.
abstract: Oxygen (O2) is required for cytochrome P450 (CYP)-dependent drug metabolism. Cytoglobin (CYGB) is a unique globin expressed exclusively in hepatic stellate cells (HSCs). However, its role in O2-dependent metabolism in neighboring hepatocytes remains unknown. This study provides evidence that CYGB in HSCs is involved in acetaminophen (N-acetyl-p-aminophenol; APAP)-induced hepatotoxicity. Serum alanine aminotransferase levels were higher in wild-type mice than in Cygb-null mice. Wild-type mice exhibited more severe hepatocyte necrosis around the central vein area compared with Cygb-null mice, thus indicating that CYGB deficiency protects against APAP-induced liver damage. Although no difference in the hepatic expression of CYP2E1, a key enzyme involved in APAP toxicity, was observed between wild-type and Cygb-null mice, the serum levels of the APAP metabolites cysteinyl-APAP and N-acetyl-cysteinyl-APAP were decreased in Cygb-null mice, suggesting reduced APAP metabolism in the livers of Cygb-null mice. In primary cultures, APAP-induced hepatocyte damage was increased by co-culturing with wild-type HSCs but not with Cygb-null HSCs. In addition, cell damage was markedly alleviated under low O2 condition (5% O2), suggesting the requirement of O2 for APAP toxicity. Carbon tetrachloride-induced liver injury (CYP2E1-dependent), but not lipopolysaccharide/D-galactosamine-induced injury (CYP2E1-independent), was similarly alleviated in Cygb-null mice. Considering the function of CYGB as O2 carrier, these results strongly support the hypothesis that HSCs are involved in the CYP2E1-mediated xenobiotic activation by augmenting O2 supply to hepatocytes. In conclusion, CYGB in HSCs contributes to the CYP-mediated metabolism of xenobiotics in hepatocytes by supplying O2 for enzymatic oxidation.
authors: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors: Yuga
authors: Y
authors: Teranishi
authors: Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors: Tsutomu
authors: T
authors: Matsubara
authors: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Kristopher W
authors: KW
authors: Krausz
authors: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors: Thi T T
authors: TT
authors: Le
authors: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Frank J
authors: FJ
authors: Gonzalez
authors: 1] Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan [2] Phoenixbio Co., Ltd, Hiroshima, Japan.
authors: Katsutoshi
authors: K
authors: Yoshizato
authors: Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors: Kazuo
authors: K
authors: Ikeda
authors: Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors: Norifumi
authors: N
authors: Kawada
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D000078842:Cytoglobin; D005914:Globins / Q000235:genetics / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity
chemical_list: C000627267:Cygb protein, mouse; D000078842:Cytoglobin; D008070:Lipopolysaccharides; D015262:Xenobiotics; D000082:Acetaminophen; D005914:Globins; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D010100:Oxygen