CYP2E1: from ASH to NASH
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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