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 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 micromol/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.
Kapur
Bhushan M
BM
Department of Clinical Pathology, Sunnybrook Health Science Centre, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada. b.kapur@utoronto.ca
Vandenbroucke
Arthur C
AC
Adamchik
Yana
Y
Lehotay
Denis C
DC
Carlen
Peter L
PL
D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000378:metabolism*; D005492:Folic Acid / Q000494:pharmacology*; D005561:Formates / Q000378:metabolism / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D000432:Methanol / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000187:drug effects; D051381:Rats; D046509:Tissue Culture Techniques
D005561:Formates; C030544:formic acid; D000431:Ethanol; D005492:Folic Acid; D000432:Methanol