Dataset Information

Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice.

ABSTRACT: Ethanol can induce cytochrome P450 2E1, an active generator of reactive oxygen species, and this cytochrome is considered a risk factor for oxidative liver injury. Recently, we found that in addition to P450 2E1 also cytochrome P450 2A5, another isoform of cytochrome P450, can be induced by ethanol, and that ethanol induction of cytochrome P450 2A5 is P450 2E1-dependent.To investigate the role of cytochrome P450 2A5 in alcohol-induced liver injury.Cytochrome P450 2A5-knockout mice and wild type mice were fed the Lieber-Decarli ethanol liquid diet to induce liver injury. Controls were fed the Lieber-Decarli control diet.After 4 weeks of feeding with Lieber-Decarli diet, ethanol-induced liver injury was enhanced in the knockout mice compared with wild type mice, as indicated by serum transaminases, hepatic fat accumulation (steatosis), and necroinflammation observed in liver sections with Haematoxylin & Eosin staining. Ethanol-induced oxidative stress was also higher in the knockout mice than the wild types. Ethanol feeding induced cytochrome P450 2A5 in wild type mice but not in the knockout mice, while induction of cytochrome P450 2E1 was comparable in the knockout and wild type mice.These results suggest that cytochrome P450 2A5 protects against ethanol-induced oxidative liver injury.

SUBMITTER: Hong F

PROVIDER: S-EPMC4442740 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice.

Hong Feng F Liu Xiyu X Ward Stephen S SS Xiong Huabao H Cederbaum Arthur I AI Lu Yongke Y

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 20150306 6

<h4>Background</h4>Ethanol can induce cytochrome P450 2E1, an active generator of reactive oxygen species, and this cytochrome is considered a risk factor for oxidative liver injury. Recently, we found that in addition to P450 2E1 also cytochrome P450 2A5, another isoform of cytochrome P450, can be induced by ethanol, and that ethanol induction of cytochrome P450 2A5 is P450 2E1-dependent.<h4>Aims</h4>To investigate the role of cytochrome P450 2A5 in alcohol-induced liver injury.<h4>Methods</h4> ...[more]

PMID: 25804444

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Project description:Vinyl chloride (VC), a common industrial organochlorine and environmental pollutant, has been shown to directly cause hepatic angiosarcoma and toxicant-associated steatohepatitis at high exposure levels. However, the impact of lower concentrations of VC on the progression of underlying liver diseases (e.g., nonalcoholic fatty liver disease [NAFLD]) is unclear. Given the high prevalence of NAFLD in the United States (and worldwide) population, this is an important concern. Recent studies by our group with VC metabolites suggest a potential interaction between VC exposure and underlying liver disease to cause enhanced damage. Here, a novel mouse model determined the effects of VC inhalation at levels below the current Occupational Safety and Health Administration limit (<1 ppm) in the context of NAFLD to better mimic human exposure and identify potential mechanisms of VC-induced liver injury. VC exposure caused no overt liver injury in mice fed a low-fat diet. However, in mice fed a high-fat diet (HFD), VC significantly increased liver damage, steatosis, and increased neutrophil infiltration. Moreover, VC further enhanced HFD-induced oxidative and endoplasmic reticulum stress. Importantly, VC exposure dysregulated energy homeostasis and impaired mitochondrial function, even in mice fed a low-fat diet. In toto, the results indicate that VC exposure causes metabolic stress that sensitizes the liver to steatohepatitis caused by HFD. Conclusion: The hypothesis that low-level (below the Occupational Safety and Health Administration limit) chronic exposure to VC by inhalation enhances liver injury caused by an HFD is supported. Importantly, our data raise concerns about the potential for overlap between fatty diets (i.e., Western diet) and exposure to VC and the health implications of this co-exposure for humans. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity. (Hepatology Communications 2018;2:270-284).

Dataset Information

Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice.

Publications

Absence of cytochrome P450 2A5 enhances alcohol-induced liver injury in mice.

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