S-adenosylmethionine decreases the peak blood alcohol levels 3 h after an acute bolus of ethanol by inducing alcohol metabolizing enzymes in the liver

Abstract

Introduction: An alcohol bolus causes the blood alcohol level (BAL) to peak at 1-2 h post ingestion. The ethanol elimination rate is regulated by alcohol metabolizing enzymes, primarily alcohol dehydrogenase (ADH1), acetaldehyde dehydrogenase (ALDH), and cytochrome P450 (CYP2E1). Recently, S-adenosylmethionine (SAMe) was found to reduce acute BALs 3 h after an alcohol bolus. The question, then, was: what is the mechanism involved in this reduction of BAL by feeding SAMe? To answer this question, we investigated the changes in ethanol metabolizing enzymes and the epigenetic changes that regulate the expression of these enzymes during acute binge drinking and chronic drinking.

Methods: Rats were fed a bolus of ethanol with or without SAMe, and were sacrificed at 3 h or 12 h after the bolus.

Results: RT-PCR and Western blot analyses showed that SAMe significantly induced ADH1 levels in the 3 h liver samples. However, SAMe did not affect the changes in ADH1 protein levels 12 h post bolus. Since SAMe is a methyl donor, it was postulated that the ADH1 gene expression up regulation at 3 h was due to a histone modification induced by methylation from methyl transferases. Dimethylated histone 3 lysine 4 (H3K4me2), a modification responsible for gene expression activation, was found to be significantly increased by SAMe at 3 h post bolus.

Conclusion: These results correlated with the low BAL found at 3 h post bolus, and support the concept that SAMe increased the gene expression to increase the elimination rate of ethanol in binge drinking by increasing H3K4me2.

Figure 1

ADH1 was up regulated in the liver of rats given SAMe 3 h and 12 h post treatment. Western blot analysis of the protein levels 3h (A) and 12 (B) post bolus. Note that SAMe induced ADH1 in the control and ethanol fed rats 3h post bolus. C and D: ADH1 mRNA levels. SAMe significantly induced ADH1 mRNA in the control and ethanol fed rats, at both 3h and 12h post bolus (Mean ± SEM, n=3-4). E and F are beta-actin staining of the same samples used as a loading control. (Mean ± SEM, n=3-4).

Figure 2

A and B: CYP2E1 protein levels in the liver of rats given SAMe 3h and 12h post treatment. C and D: CYP2E1 mRNA levels 3h and 12h post bolus C and D. Note that SAMe induced CYP2E1 gene expression in the control and ethanol fed rats 3h and 12h post bolus. (Mean ± SEM, n=3).

Figure 3

Gene expression of ALDH1a4 in the liver of rats fed an ethanol bolus 3h (A) and 12h (B). SAMe supplementation increased the ALDH1a4 gene expression at both time intervals (Mean ± SEM, n=3-4).

Figure 4

Western blot analysis of histone 3 lysine 4 and lysine 9 dimethylation (H3K4me2 and H3K9me2). Dimethylation of histone 3 lysine 4 was significantly increased in the liver of rats given SAMe and sacrificed 3h and 12h post bolus (A and B). Dimethylation of histone 3 lysine 9 was decreased by ethanol at 3h, and increased by SAMe at 3h and 12h (C and D) post bolus. (Mean ± SEM, n=3).