Increased plasma fatty acid ethyl ester levels following inhibition of oxidative metabolism of ethanol by 4-methylpyrazole treatment in human subjects.
BACKGROUND
Recent experimental evidence suggests that fatty acid ethyl esters (FAEE), nonoxidative metabolites of ethanol, mediate ethanol-induced organ damage. A direct association between pancreas-specific toxicity and increased levels of FAEE following inhibition of the oxidative metabolism of ethanol by 4-methylpyrazole (4-MP) has previously been shown in studies with rats.


METHODS
We obtained plasma samples from 32 healthy human volunteers who drank ethanol following 4-MP or placebo ingestion to determine whether in vivo inhibition of oxidative metabolism of ethanol causes a shift to nonoxidative metabolism of ethanol and the subsequent production of increased levels of FAEE. Plasma FAEE were isolated by solid-phase extraction and quantified by gas chromatography-mass spectrometry (GC-MS).


RESULTS
Plasma FAEE levels in subjects receiving 4-MP treatment before ethanol consumption were elevated compared with plasma FAEE concentrations taken from control subjects who received a placebo before ethanol ingestion. Increased FAEE levels in the 4-MP treatment group occurred after peak blood ethanol, and peak FAEE levels were achieved. There was a correlation between the blood ethanol and the plasma FAEE levels, and the correlation persisted in the presence or absence of 4-MP. The peak FAEE values were greater in men than in women, with or without 4-MP treatment.


CONCLUSIONS
Our results indicate that the in vivo inhibition of the oxidative metabolism of ethanol using 4-MP results in an increased circulating concentration of FAEE, products of the nonoxidative metabolism of ethanol.
Best
Catherine A
CA
Department of Pathology, Division of Laboratory Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Sarkola
Taisto
T
Eriksson
C J Peter
CJ
Cluette-Brown
Joanne E
JE
Laposata
Michael
M
D000328:Adult; D000931:Antidotes / Q000494:pharmacology*; D004311:Double-Blind Method; D004952:Esters / Q000097:blood*; D000431:Ethanol / Q000097:blood*; D005227:Fatty Acids / Q000097:blood*; D005260:Female; D000077604:Fomepizole; D006801:Humans; D008297:Male; D009829:Oleic Acids / Q000097:blood; D010084:Oxidation-Reduction / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D013997:Time Factors
D000931:Antidotes; D004952:Esters; D005227:Fatty Acids; D009829:Oleic Acids; D011720:Pyrazoles; D000431:Ethanol; D000077604:Fomepizole; C033180:ethyl oleate