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Lab Invest. 2015 May;95(5):515-24. doi: 10.1038/labinvest.2015.29. Epub 2015 Feb 16.

Involvement of hepatic stellate cell cytoglobin in acute hepatocyte damage through the regulation of CYP2E1-mediated xenobiotic metabolism.

Author information

1
Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
2
Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
3
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
4
1] Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan [2] Phoenixbio Co., Ltd, Hiroshima, Japan.

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.

PMID:
25686096
PMCID:
PMC6331008
DOI:
10.1038/labinvest.2015.29
[Indexed for MEDLINE]
Free PMC Article

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