Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors

Christine L. Powell, Blair U. Bradford, Christopher Patrick Craig, Masato Tsuchiya, Takeki Uehara, Thomas M. O'Connell, Igor P. Pogribny, Stepan Melnyk, Dennis R. Koop, Lisa Bleyle, David W. Threadgill, Ivan Rusyn

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalasedependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low-and high-Km aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal β-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.

Original languageEnglish (US)
Pages (from-to)131-139
Number of pages9
JournalToxicological Sciences
Volume115
Issue number1
DOIs
StatePublished - May 1 2010

Keywords

  • Acetaldehyde
  • Catalase
  • Cytochrome P4502E1
  • Peroxisome proliferator-activated receptor alpha
  • S-adenosylmethionine

ASJC Scopus subject areas

  • Toxicology

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  • Cite this

    Powell, C. L., Bradford, B. U., Craig, C. P., Tsuchiya, M., Uehara, T., O'Connell, T. M., Pogribny, I. P., Melnyk, S., Koop, D. R., Bleyle, L., Threadgill, D. W., & Rusyn, I. (2010). Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors. Toxicological Sciences, 115(1), 131-139. https://doi.org/10.1093/toxsci/kfq031