Formic Acid, a Novel Metabolite of Chronic Ethanol Abuse, Causes Neurotoxicity, Which Is Prevented by 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...

Full description

Saved in:
Bibliographic Details
Published in:Alcoholism, clinical and experimental research clinical and experimental research, 2007-12, Vol.31 (12), p.2114-2120
Main Authors: Kapur, Bhushan M., Vandenbroucke, Arthur C., Adamchik, Yana, Lehotay, Denis C., Carlen, Peter L.
Format: Article
Language:English
Subjects:
Addictive behaviors
Adult and adolescent clinical studies
Alcoholism
Alcoholism - metabolism
Alcoholism and acute alcohol poisoning
Animals
Biological and medical sciences
Cell Death - drug effects
Dose-Response Relationship, Drug
Ethanol - metabolism
Folic Acid
Folic Acid - pharmacology
Formates - metabolism
Formates - toxicity
Formic Acid
Hippocampus - drug effects
Humans
Medical sciences
Methanol
Methanol - metabolism
Microscopy, Fluorescence
Neurons - drug effects
Neurotoxicity
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Rats
Tissue Culture Techniques
Toxicology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 0.15 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.
ISSN:0145-6008
1530-0277
DOI:10.1111/j.1530-0277.2007.00541.x