Abstract

Methanol is produced endogenously in the pituitary glands of humans and is present as a congener in almost all alcoholic beverages. Ethanol and methanol are both bio-transformed by alcohol dehydrogenase; however, ethanol has greater affinity for the enzyme. Since ethanol is preferentially metabolized by the enzyme, it is not surprising that trace amounts of methanol, most likely originating from both sources, have been reported in the blood of people who drink alcohol. Toxicity resulting from methanol is very well documented in both humans and animals and is attributed to its toxic metabolite formic acid. To understand ethanol toxicity and Fetal Alcohol Spectrum Disorders, it is important to consider methanol and its metabolite, formic acid, as potential contributors to the toxic effects of alcohol.

Accumulation of methanol suggests that alcohol-drinking population should have higher than baseline levels of formic acid. Our preliminary studies do indeed show this. Chronic low-level exposure to methanol has been suggested to impair human visual functions. Formic acid is known to be toxic to the optic nerve. Ophthalmological abnormalities are a common finding in children whose mothers used alcohol during pregnancy. Formic acid, a low molecular weight substance, either crosses the placenta or may be formed in-situ from the water soluble methanol that crosses the placenta. Embryo toxicity from formic acid has been reported in an animal model

To assess neurotoxicity we applied low doses of formic acid to rat brain hippocampal slice cultures. We observed neuronal death with a time and dose response. Formic acid requires folic acid as a cofactor for its elimination. Animal studies have shown that when folate levels are low, the elimination of formic acid is slower and formate levels are elevated. When folic acid was added along with the formic acid to the brain slice cultures, neuronal death was prevented.

Therefore, folate deficient chronic drinkers may be at higher risk of organ damage. Women who are folic acid deficient and consume alcohol may have higher levels of formic acid and should they become pregnant, their fetus may be at risk. To our knowledge low level chronic exposure to formic acid and its relationship to folic acid in men or women who drink alcohol has never been studied. Our hypothesis is that the continuous exposure to low levels of formic acid is toxic to the fetus and may be part of the etiology of Fetal Alcohol Spectrum Disorders.

Folic acid slows brain damage caused by formic acid in alcohol abuse

Attention: Assignment Editor, Health/Medical Editor, Media Editor, News Editor

TORONTO, ONTARIO, MEDIA RELEASE--(Marketwire - Nov. 22, 2007) - A new study with groundbreaking public health implications for treating alcoholism and preventing Fetal Alcohol Syndrome has shown that a byproduct of methanol, a contaminant found in many alcoholic beverages, causes neurotoxicity that can be mitigated by folic acid.

Formic acid, a byproduct of methanol, is known to alter the normal functioning of the nervous system and was found in higher quantities in alcoholics. The toxicity of formic acid was significantly slowed down by administering folic acid in an animal model.

The study was led by Dr. Bhushan Kapur, Department of Clinical Pathology, Sunnybrook Health Sciences Centre in collaboration with Dr. Peter Carlen, Department of Neurosciences, Toronto Western Division of the University Health Network. Supported by a grant from the Canadian Institutes of Health Research and appearing in today's edition of Alcoholism: Clinical and Experimental Research, the study examined formic acid levels in alcoholics as compared with those in a control group. The serum formic acid levels were significantly higher in alcoholics as compared to the controls. Formic acid was not detected in the cerebrospinal fluid (a clear fluid bathing the entire surface of central nervous system) in the control group, but was found in three of the four alcoholic cases.

When the equivalent amount of formic acid that is found in alcoholics was added to rat brain slice cultures, the acid caused neuronal cell death. When folic acid was added with formic acid, neuronal cell death could be prevented.

"Our studies suggest that formic acid may indeed be the mechanism for many alcohol-related diseases, such as liver disease and central nervous system disorders," says Dr. Bhushan Kapur. "Because the neurotoxicity of formic acid can be greatly slowed by administering folic acid, which is inexpensive and readily available, the public health impact is staggering in terms of treating alcohol abusers and possibly preventing the serious affects of Fetal Alcohol Syndrome."

Dr. Kapur, also a scientist with Motherisk at the Hospital for Sick Children, notes that chronic exposure to low levels of formic acid gradually harms the body, citing that liver damage in alcoholics does not take place overnight. It is conceivable that a continuous exposure to low, but above normal, formic acid levels may be toxic to cells and contribute to alcohol-related organ damage.

This research resulted in a CIHR New Emerging Team Grants, intended to support the creation or development of teams of investigators undertaking collaborative, multidisciplinary research. Drs. Kapur and Carlen are collaborating with researchers at Queen's University on an ongoing study on folic acid supplementation as a potential therapeutic intervention in preventing Fetal Alcohol Spectrum Disorders using an animal model.

"This research will certainly raise some interesting discussions for frontline healthcare providers, including the challenges of how much folic acid to recommend per day to their patients who drink, as well as factors such as absorption of folic acid, which is poor in chronic drinkers, and also the issue of compliance in this population," adds Dr. Kapur.

Contact:
Marie Sanderson
Senior Communications Advisor
416.967.8554 or 416.480.4040
marie.sanderson@sunnybrook.ca

IN: HEALTH

For more information, please contact

Marie Sanderson, Senior Communications Advisor
Primary Phone: 416-967-8554
Secondary Phone: 416-480-4040
E-mail: marie.sanderson@sunnybrook.ca