吡唑类化合物作为酒精氧化的抑制剂及酒精研究的重要工具：一种治疗甲醇中毒的方法。
Pyrazoles as inhibitors of alcohol oxidation and as important tools in alcohol research: an approach to therapy against methanol poisoning.
作者信息
Blomstrand R, Ostling-Wintzell H, Löf A, McMartin K, Tolf B R, Hedström K G
出版信息
Proc Natl Acad Sci U S A. 1979 Jul;76(7):3499-503. doi: 10.1073/pnas.76.7.3499.
4-Methylpyrazole, in a dose producing inhibition of alcohol dehydrogenase (alcohol:NAD(+) oxidoreductase, EC 1.1.1.1), was given alone or together with ethanol (10%) as sole drinking fluid to growing rats for up to 38 weeks. Their weight curves remained normal. Electron microscopy of liver, kidney, and heart revealed no changes related to treatment. Hematologic analysis showed normal values for blood and bone marrow. Several clinical chemical parameters showed no impairment of liver or kidney function, except for an enhancement of the microsomal drug-metabolizing activity after concurrent administration of 4-methylpyrazole and ethanol. A study on rats receiving 4-methylpyrazole and ethanol indicated a mutual interaction of the two compounds or the metabolites, leading to increased concentration in the blood of the compounds and reduced formation of 4-hydroxymethylpyrazole, the primary metabolite of 4-methylpyrazole. In monkeys, elimination of 4-methylpyrazole followed a linear course. 4-Hydroxymethylpyrazole accumulated to a level of at most 10% of that of 4-methylpyrazole. Concurrent administration of methanol inhibited the elimination of 4-methylpyrazole about 25%, and 4-methylpyrazole produced a profound inhibition of the oxidation of methanol. 4-Methylpyrazole, at a level in the plasma of more than 10 muM, prevented accumulation of the toxic metabolite formic acid in methanol-poisoned monkeys, and repeated injections of 4-methylpyrazole abolished methanol toxicity in monkeys receiving lethal doses of methanol. The present investigation indicates that 4-methylpyrazole, with its low toxicity and strong inhibition of alcohol oxidation, is a valuable tool for experimental studies of alcohol metabolism and its effects. It illustrates the usefulness of the monkey as a model to study 4-methylpyrazole activity and toxicity in light of its possible use for treating methanol poisoning in human beings.
将4-甲基吡唑以能抑制乙醇脱氢酶（乙醇：NAD(+)氧化还原酶，EC 1.1.1.1）的剂量单独给予生长中的大鼠，或以10%乙醇作为唯一饮用液体同时给予生长中的大鼠，持续38周。它们的体重曲线保持正常。肝脏、肾脏和心脏的电子显微镜检查未发现与治疗相关的变化。血液学分析显示血液和骨髓的数值正常。除了同时给予4-甲基吡唑和乙醇后微粒体药物代谢活性增强外，几个临床化学参数未显示肝功能或肾功能受损。一项对接受4-甲基吡唑和乙醇的大鼠的研究表明，这两种化合物或其代谢产物之间存在相互作用，导致化合物在血液中的浓度增加，4-甲基吡唑的主要代谢产物4-羟甲基吡唑的形成减少。在猴子中，4-甲基吡唑的消除呈线性过程。4-羟甲基吡唑积累到最多为4-甲基吡唑水平的10%。同时给予甲醇可使4-甲基吡唑的消除抑制约25%，而4-甲基吡唑对甲醇的氧化有显著抑制作用。血浆中4-甲基吡唑水平超过10μM时，可防止甲醇中毒猴子体内有毒代谢产物甲酸的积累，重复注射4-甲基吡唑可消除接受致死剂量甲醇的猴子的甲醇毒性。本研究表明，4-甲基吡唑毒性低且对酒精氧化有强烈抑制作用，是酒精代谢及其影响的实验研究的有价值工具。鉴于其可能用于治疗人类甲醇中毒，本研究说明了猴子作为研究4-甲基吡唑活性和毒性的模型的有用性。
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