Formic Acid, a Novel Metabolite of Chronic Ethanol Abuse, Causes Neurotoxicity, Which Is Prevented by Folic Acid
Article first published online: 20 NOV 2007
Alcoholism: Clinical and Experimental Research
Volume 31, Issue 12, pages 2114–2120, December 2007
How to Cite
Kapur, B. M., Vandenbroucke, A. C., Adamchik, Y., Lehotay, D. C. and Carlen, P. L. (2007), Formic Acid, a Novel Metabolite of Chronic Ethanol Abuse, Causes Neurotoxicity, Which Is Prevented by Folic Acid. Alcoholism: Clinical and Experimental Research, 31: 2114–2120. doi: 10.1111/j.1530-0277.2007.00541.x
- Issue published online: 20 NOV 2007
- Article first published online: 20 NOV 2007
- Received for publication May 1, 2007; accepted September 24, 2007.
- Formic Acid;
- Folic Acid;
Background: 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.
Objective: To determine if FA levels are higher in the alcohol-drinking population and to assess its neurotoxicity in organotypic hippocampal rat brain slice cultures.
Methods: 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.
Results: 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 μmol/l) was added with the FA, neuronal death was prevented.
Conclusions: 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.