Ethanol increases mitochondrial cytochrome P450 2E1 in mouse liver and rat hepatocytes

Robin, Marie-Anne; I, Sauvage; Grandperret, T.; Descatoire, Véronique; Pessayre, Dominique; Fromenty, Bernard

doi:10.1016/j.febslet.2005.11.029

Cited by 93 publications

(83 citation statements)

References 43 publications

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“…This decline in MMP was prevented by cyclosporine A, and the BSO-induced loss of cell viability in the mE10 and mE27 cells was prevented by cyclosporine A. Importantly, ethanol was shown to elevate the levels of mitochondrial CYP2E1 in addition to the well known increase in microsomal CYP2E1 (78). It is interesting to speculate that damage to mitochondrial function and membrane potential produced by mitochondrial CYP2E1 may be an early event in liver cell injury and that mitochondrial CYP2E1 may contribute to the biochemical and toxicological effects which were previously ascribed to CYP2E1 in the endoplasmic reticulum.…”

Section: Mitochondrial Cyp2e1mentioning

confidence: 87%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

651

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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Section: Mitochondrial Cyp2e1mentioning

confidence: 87%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

651

534

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“…In addition to the respiratory chain being a significant source of mitochondrial ROS production, work by Fromenty and colleagues demonstrated an alcohol dependent increase in both microsomal and mitochondrial cytochrome P450 2E1 (CYP450 2E1) in cultured hepatocytes and liver of wild-type mice [69] suggesting an additional source of oxidants in alcohol exposed mitochondria. Indeed, CYP450 2E1 is known to be a significant source of ROS as it generates high amounts of hydrogen peroxide in the absence or presence of oxidizable co-substrates due to the "un-coupled" nature of this P450 isoform [70].…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

“…In contrast, short-term alcohol exposure did not enhance mitochondrial CYP450 2E1 levels in liver of ob/ob mice. It is important to note that there was no difference in the levels and activity of CYP450 2E1 in liver from lean and ethanol-naïve ob/ob mice [69]. Mitochondrial ROS generation has also been ascribed to several matrix enzymes including α-ketoglutarate dehydrogenase [71,72] and α-glycerophosphate dehydrogenase [73].…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

382

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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“…7 GSH levels and aniline hydroxylase activity were determined in liver homogenates prepared in 0.1 M phosphate buffer, pH 7.4, as described before. 17 Aconitase activity, which can be impaired by superoxide anion, was assessed in homogenates as previously described. 7 To evaluate whether CCl 4 treatment could induce early apoptosis, the activity of caspases 2, 3, 8 and 9 was measured using the fluorescent ApoAlert Caspase Profiling Assay Plate (Clontech, Mountain View, CA) as described before.…”

Section: Transmission Electron Microscopymentioning

confidence: 99%

Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver

Knockaert

Berson

Ribault

et al. 2012

Laboratory Investigation

Self Cite

109

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Although carbon tetrachloride (CCl 4 )-induced acute and chronic hepatotoxicity have been extensively studied, little is known about the very early in vivo effects of this organic solvent on oxidative stress and mitochondrial function. In this study, mice were treated with CCl 4 (1.5 ml/kg ie 2.38 g/kg) and parameters related to liver damage, lipid peroxidation, stress/defense and mitochondria were studied 3 h later. Some CCl 4 -intoxicated mice were also pretreated with the cytochrome P450 2E1 inhibitor diethyldithiocarbamate or the antioxidants Trolox C and dehydroepiandrosterone. CCl 4 induced a moderate elevation of aminotransferases, swelling of centrilobular hepatocytes, lipid peroxidation, reduction of cytochrome P4502E1 mRNA levels and a massive increase in mRNA expression of heme oxygenase-1 and heat shock protein 70. Moreover, CCl 4 intoxication induced a severe decrease of mitochondrial respiratory chain complex IV activity, mitochondrial DNA depletion and damage as well as ultrastructural alterations. Whereas DDTC totally or partially prevented all these hepatic toxic events, both antioxidants protected only against liver lipid peroxidation and mitochondrial damage. Taken together, our results suggest that lipid peroxidation is primarily implicated in CCl 4 -induced early mitochondrial injury. However, lipid peroxidation-independent mechanisms seem to be involved in CCl 4 -induced early hepatocyte swelling and changes in expression of stress/defense-related genes. Antioxidant therapy may not be an efficient strategy to block early liver damage after CCl 4 intoxication.

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Ethanol increases mitochondrial cytochrome P450 2E1 in mouse liver and rat hepatocytes

Cited by 93 publications

References 43 publications

CYP2E1 and oxidative liver injury by alcohol

CYP2E1 and oxidative liver injury by alcohol

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver

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