Alcohol-induced liver injury (ALI), among other molecular alterations, has been linked to abnormal liver methionine-methionine metabolism leading to decreased S-adenosylmethionine (SAM) levels. Dietary supplements containing methyl donors such as SAM and betaine attenuate ALI in animal models; however, the protective mechanisms remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress.
We hypothesized that the protective effect of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a high-fat control diet or a methyl donor-enriched diet with or without alcohol for 4 weeks using the enteral alcohol feeding model.
As expected, methyl donor supplementation attenuated ALI and increased the ratio of reduced glutathione:oxidized glutathione. Interestingly, methyl donors resulted in a 35% increase in blood alcohol elimination rate, and while there was no effect on gastric alcohol metabolism, a profound effect on liver alcohol metabolism was observed.
The catalase-dependent pathway of alcohol metabolism was induced, but the increase in CYP2E1 activity by alcohol was attenuated, possibly mitigating oxidant production. Other factors that contributed to the protective effects of methyl donors in ALI were increased activity of low- and high-K(m) aldehyde dehydrogenases, resulting in lower hepatic acetaldehyde, maintenance of efficient mitochondrial energy metabolism, and promotion of peroxisomal beta-oxidation.
Profound changes in alcohol metabolism represent another important mechanism of the protective effect of methyl donors in ALI.
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