Metabolism of ethanol and carcinogens by glutathione transferases.

Abstract

Nonoxidative alcohol metabolism to form fatty acid ethyl esters contributes to alcohol-related end-organ damage, and these products are formed by two synthase enzymes. We recently purified the major (pI 4.9) synthase from human myocardium. The N-terminal sequence (A P Y T V V Y F P V R G R X K A L R M L X A D) is greater than 73% identical with that of a neutral (pI 6.7) detoxification enzyme, glutathione transferase P from rat hepatocellular carcinoma (P P Y T I V Y F P V R G R C E A T R M L L A D). Moreover, both the major human fatty acid ethyl ester synthase and bovine liver glutathione transferase catalyze the formation of fatty acid ethyl esters (Vmax 105 and 98 nmol per hr per mg, respectively). In addition, both enzymes catalyze the formation of glutathione-xenobiotic conjugates (Vmax 67 and 335 mol per hr per mol of enzyme, respectively). Physiological concentrations of glutathione increase the rate of formation of fatty acid ethyl esters up to 5-fold, and the glutathione transferase substrate 1-chloro-2,4-dinitrobenzene is a potent inhibitor of human myocardial fatty acid ethyl ester synthase. Thus, the identification of the major form of human myocardial fatty acid ethyl ester synthase as an acidic glutathione transferase links alcohol and xenobiotic metabolism and may relate the enhancement of tumorigenesis by alcohol abuse with carcinogen-conjugation reactions.

• Authors: P S Bora, C A Spilburg, L G Lange
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 86 Issue 12 Pg. 4470-3 (Jun 1989) ISSN: 0027-8424 [Print] United States
• PMID: 2734299 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Ethanol
• Acyltransferases
• Glutathione Transferase
• fatty acyl ethyl ester synthase

Topics

• Acyltransferases (genetics, isolation & purification, metabolism)
• Amino Acid Sequence
• Animals
• Cattle
• Ethanol (metabolism)
• Glutathione Transferase (genetics, metabolism)
• Humans
• Kinetics
• Liver (enzymology)
• Liver Neoplasms, Experimental (enzymology)
• Molecular Sequence Data
• Myocardium (enzymology)
• Organ Specificity
• Rats
• Sequence Homology, Nucleic Acid
• Species Specificity