FATTY ACID ETHYL ESTERS: BIOLOGICAL MARKERS OF ALCOHOL

不像零阶代谢物，乙醛、脂肪酸乙基

Unlike the zero order metabolite, acetaldehyde, fatty acid ethyl esters (FAEE) are first order direct, nonoxidative metabolites of ethanol described in our laboratory in 1981 to be formed by the enzyme FAEE synthase. Our extensive methodological development for extraction and quantitation of these lipids from biological samples has led to the observation that FAEE are formed in vivo in adipose tissue and bone marrow and have a half- life of approximately 24 hours, much longer than that of ethanol. In preliminary experiments, concentrations as high as 5400 nmol/g occur in rabbit adipose tissue and bone marrow with a limit of detectability of 2 nmol/g; similarly, autopsy studies disclose the presence of these alcohol metabolites in adipose tissues of drinkers. In a pilot clinical study, quantitation of bone marrow FAEE allowed the correct diagnosis of alcohol consumption to be made as long as six days after ingestion in four out of five alcohol consumers, and in eight out of eight controls. No false positives were thus detected. Importantly, FAEE synthase activity has been quantitated in peripheral human leukocytes. Proposed studies therefore will characterize the usefulness of the ratio of adipose tissue and bone marrow FAEE concentration to leukocyte FAEE synthase activity as biological markers of alcohol consumption that is independent of polymorphisms in synthase activity. First, the time course and concentration of adipose tissue and bone marrow FAEE will be quantitated in rabbits fed various amounts of ethanol for up to three months and values normalized to leukocyte FAEE synthase activity. Adipose tissue FAEE synthase will be characterized. Human studies will consist of adipose tissue FAEE quantitation in 800 patients undergoing routine general surgery and results correlated to those obtained by a standard questionnaire to assess frequency, duration and quantity of recent alcohol use. Pharmacokinetic analyses of buttock adipose tissue obtained by skinny needle aspiration and bone marrow FAEE will be performed in forty patients administered ethanol in the Clinical Research Center with normalization of FAEE concentrations to peripheral leukocyte FAEE synthase activity. These data will establish the quantitative usefulness of a tissue FAEE/leukocyte synthase index as a marker of alcohol consumption for use in diagnostic medical evaluations, forensic cases, high risk job holders, and surveillance in problem drinkers who deny alcohol ingestion.