Endogenous Methanol Regulates Mammalian Gene Activity

We recently showed that methanol emitted by wounded plants might function as a signaling molecule for plant-to-plant and plant-to-animal communications. In mammals, methanol is considered a poison because the enzyme alcohol dehydrogenase (ADH) converts methanol into toxic formaldehyde. However, the detection of methanol in the blood and exhaled air of healthy volunteers suggests that methanol may be a chemical with specific functions rather than a metabolic waste product. Using a genome-wide analysis of the mouse brain, we demonstrated that an increase in blood methanol concentration led to a change in the accumulation of mRNAs from genes primarily involved in detoxification processes and regulation of the alcohol/aldehyde dehydrogenases gene cluster. To test the role of ADH in the maintenance of low methanol concentration 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 methanol, ethanol and formaldehyde concentrations. Removal of the intestine significantly decreased the rate of methanol addition to the plasma and suggested that the gut flora may be involved in the endogenous production of methanol. ADH in the liver was identified as the main enzyme for metabolizing methanol because an increase in the methanol and ethanol contents in the liver homogenate was observed after 4-MP administration into the portal vein. Liver mRNA quantification showed changes in the accumulation of mRNAs from genes involved in cell signalling and detoxification processes. We hypothesized that endogenous methanol acts as a regulator of homeostasis by controlling the mRNA synthesis.我们此前的研究表明，受损植物释放的甲醇可作为信号分子，参与植物间以及植物与动物间的信号交流。在哺乳动物体内，甲醇通常被视为有毒物质，这是因为乙醇脱氢酶（alcohol dehydrogenase，ADH）可将甲醇转化为具有毒性的甲醛。但在健康志愿者的血液与呼出气体中检测到甲醇的事实表明，甲醇或许并非代谢废物，而是具备特定生理功能的化学物质。通过对小鼠脑组织进行全基因组分析，我们证实血液甲醇浓度升高会导致主要参与解毒过程以及乙醇/醛脱氢酶基因簇调控的基因的mRNA积累量发生改变。为探究乙醇脱氢酶（ADH）在维持血浆低浓度甲醇中的作用，我们使用了特异性ADH抑制剂4-甲基吡唑（4-methylpyrazole，4-MP），实验结果显示，腹腔给予4-MP可显著提升血浆中甲醇、乙醇与甲醛的浓度。摘除肠道可显著降低血浆甲醇的生成速率，这提示肠道菌群可能参与了内源性甲醇的产生过程。经门静脉给予4-MP后，肝脏匀浆中的甲醇与乙醇含量出现升高，由此确认肝脏中的乙醇脱氢酶是代谢甲醇的主要酶类。肝脏mRNA定量分析结果显示，参与细胞信号传导与解毒过程的基因的mRNA积累量发生了变化。我们据此提出假说：内源性甲醇可通过调控mRNA合成，作为稳态调节因子发挥作用。