Involvement of hepatic stellate cell cytoglobin in acute hepatocyte damage through the regulation of CYP2E1-mediated xenobiotic metabolism.
Involvement of hepatic stellate cell cytoglobin in acute hepatocyte damage through the regulation of CYP2E1-mediated xenobiotic metabolism.
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DOI：
10.1038/labinvest.2015.29
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Kawada N
中科院分区：
文献类型：
--
作者：
Teranishi Y;Matsubara T;Krausz KW;Le TT;Gonzalez FJ;Yoshizato K;Ikeda K;Kawada N
氧（O2）是细胞色素P450（CYP）依赖性药物代谢所必需的。细胞珠蛋白（CYGB）是一种特异性表达于肝星状细胞（HSC）的珠蛋白。然而，其在邻近肝细胞中的O2依赖性代谢中的作用仍然未知。这项研究提供的证据表明，CYGB在HSC参与对乙酰氨基酚（N-乙酰基-对氨基苯酚; APAP）诱导的肝毒性。野生型小鼠血清丙氨酸氨基转移酶水平高于CYGB基因敲除小鼠。与CYGB缺失小鼠相比，野生型小鼠在中央静脉区域周围表现出更严重的肝细胞坏死，从而表明CYGB缺乏可防止APAP诱导的肝损伤。尽管在野生型和CYGB缺失小鼠之间未观察到APAP毒性中涉及的关键酶CYP 2 E1的肝脏表达存在差异，但CYGB缺失小鼠中APAP代谢物半胱氨酰-APAP和N-乙酰基-半胱氨酰- APAP的血清水平降低，表明CYGB缺失小鼠肝脏中APAP代谢降低。在原代培养物中，APAP诱导的肝细胞损伤通过与野生型HSC共培养而增加，但与CYGB缺失的HSC不增加。此外，在低O2条件下（5%O2），细胞损伤明显减轻，表明O2的APAP毒性的需要。四氯化碳诱导的肝损伤（CYP 2 E1依赖性），而不是脂多糖/D-半乳糖胺诱导的损伤（CYP 2 E1非依赖性），在CYGB-null小鼠中同样减轻。考虑到CYGB作为O2载体的功能，这些结果有力地支持了HSC通过增加O2供应而参与CYP 2 E1介导的外源性激活的假设。总之，肝星状细胞中的CYGB通过为酶促氧化提供O2，促进CYP介导的外源性物质在肝细胞中的代谢。
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.
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