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Inhibition of cytochrome P4502E1 by chlormethiazole attenuated acute ethanol-induced fatty liver
•CMZ pretreatment attenuated acute ethanol-induced fatty liver in mice.•CMZ suppressed acute ethanol-induced oxidative stress via CYP2E1 inhibition.•CMZ suppressed acute ethanol-induced decline of serum adiponectin level.•CM pretreatment led to the further activation of autophagy. Cytochrome P4502E1...
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Published in: | Chemico-biological interactions 2014-10, Vol.222, p.18-26 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | •CMZ pretreatment attenuated acute ethanol-induced fatty liver in mice.•CMZ suppressed acute ethanol-induced oxidative stress via CYP2E1 inhibition.•CMZ suppressed acute ethanol-induced decline of serum adiponectin level.•CM pretreatment led to the further activation of autophagy.
Cytochrome P4502E1 (CYP2E1) has been demonstrated to play crucial roles in chronic ethanol-induced fatty liver, while its role in acute ethanol-induced fatty liver remains unclear. The current study was designed to evaluate the effects of chlormethiazole (CMZ), a specific inhibitor of CYP2E1, on acute ethanol-induced fatty liver, and to explore the mechanisms. Mice were pretreated with single dose of CMZ (50mg/kg body weight) by intraperitoneal injection or equal volume of saline, and then exposed to three doses of ethanol (5g/kg body weight, 25%, w/v) by gavage with 12h intervals. The mice were sacrificed at 4h after the last ethanol dosing. It was found that CMZ significantly attenuated acute ethanol-induced increase of the hepatic and serum triglyceride levels, and reduced fat droplets accumulation in mice liver. Acute ethanol-induced increase of the hepatic malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels (two biomarkers for oxidative stress) and decrease of glutathione (GSH) level was significantly suppressed by CMZ. CMZ also suppressed ethanol-induced decline of serum adiponectin level, but did not significantly affect the serum tumor necrosis factor-α (TNF-α) and ethanol levels. Furthermore, a significant decline of p62 protein level was observed in CMZ/ethanol group mice liver compared with that of the ethanol group mice. However, acute ethanol-induced increase of peroxisome proliferator-activated receptor α (PPAR-α) protein level was suppressed by CMZ, while the protein levels of sterol regulatory element-binding protein-1c (SREBP-1) and diacylglycerol acyltransferase 2 (DGAT2) were not significantly affected by ethanol or CMZ. Collectively, the results of the current study demonstrated that CMZ could effectively attenuate acute ethanol-induced fatty liver possibly by suppressing oxidative stress and adiponectin decline, and activating autophagy, which suggest that CYP2E1 might also play important roles in acute ethanol-induced fatty liver. |
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ISSN: | 0009-2797 1872-7786 |
DOI: | 10.1016/j.cbi.2014.08.009 |