Ethanol exposure modulates hepatic S-adenosylmethionine and S-adenosylhomocysteine levels in the isolated perfused rat liver through changes in the redox state of the NADH/NAD+ system

Abstract

Methionine metabolism is disrupted in patients with alcoholic liver disease, resulting in altered hepatic concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and other metabolites. The present study tested the hypothesis that reductive stress mediates the effects of ethanol on liver methionine metabolism. Isolated rat livers were perfused with ethanol or propanol to induce a reductive stress by increasing the NADH/NAD+ ratio, and the concentrations of SAM and SAH in the liver tissue were determined by high-performance liquid chromatography. The increase in the NADH/NAD+ ratio induced by ethanol or propanol was associated with a marked decrease in SAM and an increase in SAH liver content. 4-Methylpyrazole, an inhibitor the NAD+-dependent enzyme alcohol dehydrogenase, blocked the increase in the NADH/NAD+ ratio and prevented the alterations in SAM and SAH. Similarly, co-infusion of pyruvate, which is metabolized by the NADH-dependent enzyme lactate dehydrogenase, restored the NADH/NAD+ ratio and normalized SAM and SAH levels. The data establish an initial link between the effects of ethanol on the NADH/NAD+ redox couple and the effects of ethanol on methionine metabolism in the liver.

Resveratrol attenuates excessive ethanol exposure induced insulin resistance in rats via improving NAD+/NADH ratio

“…However, whether Res could improve ethanol-induced insulin resistance via up-regulating the ratio of NAD + /NADH and its potential mechanisms remain to be clarified. Research from Watson et al demonstrates that the ethanol-induced reduction in NAD + /NADH ratio through the accumulation of NADH is largely due to the activation of ADH, as a normalized ratio of NAD + /NADH is observed upon co-treatment with an inhibitor of ADH-4-methylpyrazole [12]. In our study, Res treatment apparently inactivated ADH, which retarded the conversion of NAD + to NADH, resultantly rescuing the down-regulated NAD + /NADH ratio from ethanol exposure.…”

“…A high level of hepatic NAD + activates hepatic SIRT1 in rats fed with proanthocyanidins [10], while research by Chen et al indicates that under caloric restriction, a low NAD + /NADH ratio in mice liver could constrain the expression and activity of SIRT1 [11]. Meanwhile, abundant evidence implies that the metabolism of ethanol in the liver accumulates NADH but reduce NAD + , thus significantly decreasing NAD + /NADH ratio [8,12]. Accordingly, we hypothesized that ethanol suppressed SIRT1 through decreasing the ratio of NAD + /NADH [8], consequently leading to insulin resistance.…”

S‐Adenosylhomocysteine Inhibits NF‐κB‐Mediated Gene Expression in Hepatocytes and Confers Sensitivity to TNF Cytotoxicity

“…SAH was extracted in 5% metaphosphoric acid and measured by high‐performance liquid chromatography as described previously (Watson et al., ).…”

Alcohol Drinking Patterns and Nutrition in Alcoholic Liver Disease

“…Especially the decreased uptake of methionine but also the inhibition of the methionine synthase in combination with the deficiency of folic acid and pyridoxine has been shown to be a critical factor in the development and progression of alcoholic liver disease. Recent data from animal studies suggest that the shift in the NADH/ NAD + ratio resulting from alcohol metabolism may also affect liver methionine metabolism (Watson et al 2011). Indeed, it has been shown that the supplementation of methionine but also its metabolite S-adenosyl-L-methinone may improve alcoholic liver disease (for overview also see Beier and McClain (2010)).…”