ИСТИНА

Methanol (MeOH) and formaldehyde accumulate in the blood of healthy mammals under certain conditions. The first major source of MeOH is a fresh fruit and vegetable diet: it results from the function of pectin methylesterase derived from plant cell walls and gut bacteria. At the same time, blockage of alcohol dehydrogenase class 1 (ADH1) by 4-methylpyrazol (4-MP) leads to rapid MeOH accumulation in the blood of humans and mice, which suggests the presence of an endogenous source of MeOH. The demethylation of biopolymers is an alternative method for MeOH production in mammals. To examine whether MeOH could be produced by bacteria-free organs, we performed an experiment using an isolated perfused rat liver system. Injection of 4-MP after MeOH injection (120 mg/kg) triggered a slight increase in the concentration of MeOH in reperfused liquids. However, 4-MP by itself did not lead to MeOH accumulation. Thus, we concluded that isolated liver cannot produce MeOH by itself and that biopolymer demethylation may have a small impact on endogenous MeOH synthesis. In addition to MeOH production, we studied MeOH metabolism in mice by using an aldehyde dehydrogenase 2 (ALDH2) inhibitor (disulfiram, DSF) and an ALDH2 activator (alpha-lipoic acid, ALA) after ethanol administration. The ethanol (EtOH) and MeOH concentrations became much higher than the acetaldehyde concentration after the inhibition of ALDH2. The activation of ALDH2 by ALA also increased the MeOH and EtOH levels, but the acetaldehyde concentration remained the same. Injection of DSF and ALA enhanced CYP2E1 (286.9±67.3-fold) and ADH1 (390.6±69.6-fold) mRNA synthesis in mouse brain tissues, however, had a little effect on CYP2E1 (9.7±0.5-fold) and ADH1 (1.2±0.3-fold) mRNA synthesis in mouse liver tissues. Thus, we showed that MeOH accumulates after ALA and DSF injection and led to dramatic changes in the gene expression of alcohol-metabolising genes in mouse brain tissues. We concluded that endogenous metabolic MeOH may function as a signal molecule for gene activation in mammalian brains.