Kapur Bhushan M, Vandenbroucke Arthur C, Adamchik Yana, Lehotay Denis C, Carlen Peter L
Department of Clinical Pathology, Sunnybrook Health Science Centre, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Alcohol Clin Exp Res. 2007 Dec;31(12):2114-20. doi: 10.1111/j.1530-0277.2007.00541.x.
Methanol is endogenously formed in the brain and is present as a congener in most alcoholic beverages. Because ethanol is preferentially metabolized over methanol (MeOH) by alcohol dehydrogenase, it is not surprising that MeOH accumulates in the alcohol-abusing population. This suggests that the alcohol-drinking population will have higher levels of MeOH's neurotoxic metabolite, formic acid (FA). FA elimination is mediated by folic acid. Neurotoxicity is a common result of chronic alcoholism. This study shows for the first time that FA, found in chronic alcoholics, is neurotoxic and this toxicity can be mitigated by folic acid administration.
To determine if FA levels are higher in the alcohol-drinking population and to assess its neurotoxicity in organotypic hippocampal rat brain slice cultures.
Serum and CSF FA was measured in samples from both ethanol abusing and control patients, who presented to a hospital emergency department. FA's neurotoxicity and its reversibility by folic acid were assessed using organotypic rat brain hippocampal slice cultures using clinically relevant concentrations.
Serum FA levels in the alcoholics (mean +/- SE: 0.416 +/- 0.093 mmol/l, n = 23) were significantly higher than in controls (mean +/- SE: 0.154 +/- 0.009 mmol/l, n = 82) (p < 0.0002). FA was not detected in the controls' CSF (n = 20), whereas it was >0.15 mmol/l in CSF of 3 of the 4 alcoholic cases. Low doses of FA from 1 to 5 mmol/l added for 24, 48 or 72 hours to the rat brain slice cultures caused neuronal death as measured by propidium iodide staining. When folic acid (1 micromol/l) was added with the FA, neuronal death was prevented.
Formic acid may be a significant factor in the neurotoxicity of ethanol abuse. This neurotoxicity can be mitigated by folic acid administration at a clinically relevant dose.
甲醇在大脑中内源性生成，且在大多数酒精饮料中作为同系物存在。由于乙醇比甲醇（MeOH）更易被乙醇脱氢酶代谢，因此甲醇在酗酒人群中蓄积并不奇怪。这表明饮酒人群中甲醇的神经毒性代谢产物甲酸（FA）水平会更高。甲酸的清除由叶酸介导。神经毒性是慢性酒精中毒的常见后果。本研究首次表明，慢性酒精中毒患者体内的甲酸具有神经毒性，而补充叶酸可减轻这种毒性。
确定饮酒人群中甲酸水平是否更高，并评估其在大鼠海马脑片器官型培养物中的神经毒性。
对送至医院急诊科的乙醇滥用患者和对照患者的样本进行血清和脑脊液甲酸测定。使用临床相关浓度，通过大鼠脑海马脑片器官型培养物评估甲酸的神经毒性及其被叶酸逆转的情况。
酗酒者的血清甲酸水平（均值±标准误：0.416±0.093 mmol/L，n = 23）显著高于对照组（均值±标准误：0.154±0.009 mmol/L，n = 82）（p < 0.0002）。对照组脑脊液（n = 20）中未检测到甲酸，而4例酗酒者中有3例脑脊液中的甲酸浓度>0.15 mmol/L。向大鼠脑片培养物中添加1至5 mmol/L的低剂量甲酸24、48或72小时，通过碘化丙啶染色测定可导致神经元死亡。当与甲酸一起添加叶酸（1 μmol/L）时，可防止神经元死亡。
甲酸可能是乙醇滥用导致神经毒性的一个重要因素。临床相关剂量的叶酸给药可减轻这种神经毒性。
