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CYP-2E1 Inhibitors Partially Ameliorate the Changes in Hepatic Fatty Acid Composition Induced in Rats by Chronic Administration of Ethanol and a High Fat Diet^1,2,3,

Michio Morimoto^*, Ronald C. Reitz, Robert J. Morin^*, Khoa Nguyen^*, Magnus Ingelman-Sundberg^** and Samuel W. French^*,4

^* Department of Pathology, Harbor UCLA Medical Center, Torrance CA 90509 Department of Biochemistry, University of Nevada, Reno, NE ^** Department of Physiological Chemistry, Karolinska Institute, Stockholm, Sweden

The objective of this study was to determine if ethanol-induced cytochrome P450 2E1 (CYP2E1) was responsible for the changes in hepatic fatty acids observed in rats fed ethanol intragastrically. We hypothesized that if CYP2E1 was responsible for these changes then CYP2E1 inhibitors fed with ethanol should prevent the ethanol-induced changes in fatty acids. We compared the fatty acid composition of the liver in rats fed ethanol alone with that in rats fed ethanol with the CYP2E1 inhibitors, diallyl sulfide and phenethyl isothiocyanate. In each experiment, rats pair-fed isocaloric glucose were included to determine the effect of the inhibitors alone on the hepatic fatty acid composition. The lobular distribution of succinic dehydrogenase was determined histochemically because the lobular distribution of CYP2E1 shifts to the periportal area in livers of rats fed CYP2E1 inhibitors. The CYP2E1 inhibitors ameliorated both the ethanol-induced changes in fatty acids and the shift in succinic dehydrogenase. Rats fed ethanol but no inhibitors had significantly greater hepatic total fatty acids and triglyceride fractions than when inhibitors were fed ethanol. Ethanol altered the fatty acid composition compared with rats fed ethanol with CYP2E1 inhibitors. The ratio of 20:4/18:2 was significantly lower and that of 18:1/18:0 was greater in alcohol-fed rats compared with their pair-fed controls. The CYP2E1 inhibitors inhibited many of the above effects of alcohol. The data suggest that the changes in the fatty acid composition due to ethanol ingestion are the result of CYP2E1-dependent lipid peroxidation and fatty acid metabolism.

KEY WORDS: • alcohol • cytochrome P450 2E1 • hepatic fatty acids • rats

¹ Supported by a grant from NIH-NIAAA 8116.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ These results were reported in part at the June 1994 Meeting of the Research on Alcoholism Society in Hawaii. The abstract was published as follows: Morimoto, M., Reitz, R., Hagbjörk, A.-L., Ingelman-Sundberg, M., Fu, P., French, S. W. (1994) Effect of Cytochrome P450 2E1 (CYP2E1) induction on the fatty acid composition of the liver in ethanol fed rats. Alcoholism: Clin. Exp. Res. 18: 512.

⁴ To whom correspondence should be addressed.

Manuscript received 18 November 1994. Revision accepted 9 August 1995.