Elsevier

Hepatology Research

Volume 28, Issue 1, January 2004, Pages 1-11
Hepatology Research

CYP2E1: from ASH to NASH

https://doi.org/10.1016/j.hepres.2003.08.001Get rights and content

Abstract

The pathology of the liver in alcoholic steatosis and alcoholic steatohepatitis (ASH) is remarkably similar to that of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), suggesting some common pathogenic mechanism. Studies carried out over the last three decades of possible mechanisms involved revealed one common link, namely the induction of cytochrome P4502E1. Its substrates include fatty acids, ketones and ethanol. These substances, when present chronically in large amounts, induce the activity of the enzyme which thereby contributes to the disposition of these substrates. This reaction, however, is associated with the release of free radicals which can cause lipid peroxidation and liver injury, including mitochondrial damage. Mitochondrial damage in turn exacerbates the oxidative stress. CYP2E1 can also convert various xenobiotics to toxic metabolites. When unchecked, this toxicity eventually results in inflammation and fibrosis, culminating in cirrhosis. Prevention of this disorder is based on limiting the substrates that induce the system, such as excessive fatty acid associated with obesity and excessive alcohol consumption. No effective pharmacologic treatment is presently available but there is ongoing research on possible inhibitors of CYP2E1, innocuous enough to be suitable for chronic human consumption and sufficiently effective to attenuate the CYP2E1 induction to avoid the consequences of its excessive activity while maintaining its physiologic role.

Section snippets

Role of alcohol dehydrogenase

Until 35 years ago, it was believed that there was only one significant pathway for ethanol metabolism, involving multiple forms of alcohol dehydrogenase (ADH), an enzyme of the cytosol that catalyzes the conversion of ethanol to acetaldehyde, coupled with the reduction of NAD+ to NADH (Fig. 1), which results in a strikingly altered NAD/NADH ratio and associated redox changes, shown to be responsible for many metabolic effects of ethanol [1], [2]. This mechanism was corroborated in the case of

Differentiation of the MEOS from ADH and catalase

Eventually, MEOS was solubilized and separated from ADH and catalase activities by diethylaminoethyl cellulose column chromatography [42], [43]. Furthermore, whereas catalase reacts peroxidatically primarily with methanol and ethanol, but not with alcohols of longer aliphatic chains [44], the NADPH-dependent MEOS was found capable of metabolizing n-propanol as well as n-butanol. This was shown in hepatic microsomal preparations and in reconstituted systems that contained the microsomal

“Ethanol-specific” cytochrome P450

That chronic ethanol consumption results in the induction of a unique P450 enzyme was shown by Ohnishi and Lieber [48] using a liver microsomal P450 fraction isolated from ethanol-treated rats. An ethanol-inducible form of P450 (LM-3a) was purified from rabbit liver microsomes which catalyzed ethanol oxidation at rates much higher than other P450 isozymes [55], [56]. Similar results have been obtained with cytochrome P450j, a major hepatic P450 isozyme purified from ethanol- or

Polymorphism of CYP2E1

Several polymorphic sites in the 5′-flanking region of the human cytochrome 2E1 gene have been reported. Indeed, it contains several restriction fragment length polymorphisms that may affect transcriptional regulation or the functional activity of the expressed protein [65], [66], [67], [68], [69], [70]. Two nucleotide exchanges are within restriction sites (PstI and RsaI) and were found to be in complete linkage disequilibrium. The RsaI sites in the regulatory 5′-flanking region described in

Regulation of CYP2E1 expression and role of cytochrome P450 other than CYP2E1 in the activity of MEOS

The rat hepatic CYP2E1 gene is transcriptionally activated within 1 day after birth [81]. This activation is accompanied by a demethylation of cytosine residues located within the 5′-flanking region of the gene, suggesting that methylation of specific residues in the 2E1 gene is responsible for the lack of transcription of the 2E1 gene in fetal liver. Cytochrome P4502E1 remains relatively stable during the remainder of the life span, and a tissue-specific relation between the hypomethylation of

Physiological role of CYP2E1 and possible therapeutic intervention in ASH and NASH

CYP2E1 is highly conserved within the human population, suggesting significant physiological function. Indeed, there appears to be a dual physiological role of CYP2E1 (Fig. 4), namely one of detoxification and one of nutritional support. That CYP2E1 contributes to the defense mechanisms of the body against the penetration of toxic xenobiotics is suggested by its location and inducibility at port of entries into the body, and by its broad substrate specificity. Indeed, consistent with such a

Conclusions

CYP2E1 plays a useful physiologic role when starvation and/or low carbohydrate diets prevail because of its contribution to the metabolism of fatty acids and its capacity to convert ketones to glucose. Furthermore, although it can activate some xenobiotics to toxic agents as well as carcinogens, it helps detoxify other xenobiotics and it also clears alcohol from the blood when ethanol reaches relatively high levels, particularly on a chronic basis, which triggers an adaptive CYP2E1 response to

Acknowledgements

The skillful editorial contributions of L.M. DeCarli and F. DeMara and the excellent secretarial assistance of Y. Rodriguez are much appreciated. Original studies were supported, in part, by NIH grant AA11115, the Department of Veterans Affairs and the Kingsbridge and Smithers Research Foundations.

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