ИСТИНА

Methanol (MeOH) is poisonous to humans because the enzyme alcohol dehydrogenase (ADH) converts MeOH in toxic formaldehyde (FA), which is then converted into formic acid by using aldehyde dehydrogenase (AlDH). The detection of MeOH in the blood of healthy mammals and humans (1) suggests that MeOH could be a substance with specific functions in mammals and humans and not simply a waste product of cell metabolism (2). Here, we directly demonstrate that an increase in the MeOH concentration in mouse and rat blood led to a change in the accumulation of mRNAs from genes primarily involved in detoxification processes and the regulation of the ADH/AlDH gene cluster. To test the role of ADH in the maintenance of low MeOH levels in the plasma, we used the specific ADH inhibitor 4-methylpyrazole (4-MP) and showed that intraperitoneal administration of 4-MP resulted in a significant increase in the plasma concentrations of MeOH, ethanol and FA. Removal of the intestine significantly decreased the rate of MeOH accumulation to the plasma, suggesting that the gut flora may be involved in the endogenous production of MeOH. However, data from the rat liver perfusion system did not support the hypothesis that this organ participates in the generation of endogenous MeOH, but liver ADH and AlDH were identified as the primary enzymes for metabolising MeOH because an increase in the MeOH and ethanol levels in the liver homogenate was observed after 4-MP administration into the portal vein. Quantification of the liver mRNA levels showed changes in the accumulation of mRNAs from genes involved in cell signalling and detoxification processes. We also confirmed the involvement of lipoic acid in the detoxification process of ethanol and MeOH. Lipoic acid has the potential to boost the accumulation of AlDH mRNA and mitochondrial ALDH-2 activity, both of which accelerate the conversion of FA to formic acid. We hypothesised that endogenous MeOH acts as a regulator of homeostasis by controlling mRNA synthesis. Although MeOH may be exhaled into the air as a waste product (similar to carbon dioxide), this chemical may also influence biochemical processes important for cellular function. References 1. Dorokhov Y.L., et al. (2012). Methanol may function as a cross-kingdom signal. PLoS One 7(4):e36122. 2. Komarova T.V., et al. (2014). Endogenous methanol regulates mammalian gene activity. PLoS One 9(2): e90239.