The Effect of Chronic Alcohol Intake Upon the Hepatic Microsomal Carcinogen-activation System

Capel, Ifor D.; Jenner, M.; Pinnock, Marisa H.; Williams, Donald C.

doi:10.1159/000225278

Cited by 31 publications

(6 citation statements)

References 8 publications

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“…Moreover, chronic ethanol ingestion has a carcinogenic enhancing effect for tumors of various tissues induced by polycyclic hydrocarbons and nitrosamines (2,3). Our laboratory has recently established a biochemical link between alcohol and carcinogen metabolism by reporting a high degree of homology between the major fatty acid ethyl ester (FAEE)' synthase from human myocardium and the glu-tathione (GSH) S-transferases, or GSTs, enzymes that detoxify a wide variety of polycyclic carcinogens and xenobiotics (4).…”

Section: Introductionmentioning

confidence: 99%

Identification of a satellite fatty acid ethyl ester synthase from human myocardium as a glutathione S-transferase.

Bora¹,

Spilburg²,

Lange³

1989

J. Clin. Invest.

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Nonoxidative alcohol metabolism catalyzed by fatty acid ethyl ester (FAEE) synthases may contribute to extrahepatic injury resulting from alcohol abuse. Unlike rabbit myocardial FAEE synthase, that from human heart has a satellite minor synthase (I) eluting from DEAE cellulose at a conductivity of 5 mS. Synthase I was purified 1,1 18-fold to homogeneity by sequential gel permeation, hydrophobic interaction, and Superose-12 fast-protein liquid chromatographies. SDS-PAGE showed a single polypeptide with a molecular mass of 26 kD and gel permeation chromatography indicated a molecular mass of 52 kD for the active enzyme. Homogeneous synthase I catalyzed ethyl ester synthesis at highest rates with unsaturated octadecanoic fatty acid substrates. The amino acid composition of synthase I was highly homologous to that of human myocardial major synthase, recently identified as an acidic glutathione (GSH) S-transferase. Antibody raised against homogeneous human heart major synthase cross-reacted with the 26-kD synthase I. FAEE synthase co-chromatographed with GSH S-transferase on DEAE cellulose, Sephadex G-100 and S-hexylglutathione agarose, and also displayed GSH S-transferase activity in catalyzing the conjugation of GSH with nitrobenzene-containing carcinogens. Thus, human myocardium contains a satellite peak of FAEE synthase activity and it is a neutral GSH S-transferase.

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Section: Introductionmentioning

confidence: 99%

Identification of a satellite fatty acid ethyl ester synthase from human myocardium as a glutathione S-transferase.

Bora¹,

Spilburg²,

Lange³

1989

J. Clin. Invest.

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“…In a previous experiment [4,5] the effect of alcohol intake upon the enzyme systems concern ed with the activation and detoxication of carcinogens was investigated. It was found that, at the dose levels employed, ethanol decreased DNA binding of benzo(a)pyrene but the number of tumors induced by this carcinogen exceeded those in the control group.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Chronic Ethanol Intake on the Growth and Spread of Some Murine Tumors

Capel¹,

Jenner²,

Pinnock³

et al. 1978

Oncology

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The effect of chronic ethanol intake on the growth and spread of some murine tumors has been investigated. The treatment had no effect on the B 16 melanoma but tended to decrease the number of Ehrlich ascites cells. In the case of the Lewis lung carcinoma, administration of ethanol for two weeks tended to lower the number of metastases to the lung without significantly affecting the primary tumor size, whereas more prolonged ethanol intake decreased the weight of the primary tumor in addition to decreasing its dissemination.

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“…Since FAEE synthase is a very anionic protein and, indeed, was first recognized by its ability to bind tightly to DEAE-cellulose at neutral pH, our studies identify this main FAEE synthase as one of the first members of the acidic class of GSH transferases to be purified to homogeneity. (31,32). Our results suggest that hepatic GSH transferases constitute an important system for ethanol elimination and thus establish a biochemical link between alcohol, xenobiotic, and carcinogen metabolism that must be taken into account in understanding drug-induced hepatic neoplasia.…”

mentioning

confidence: 99%

Metabolism of ethanol and carcinogens by glutathione transferases.

Bora

Spilburg²,

Lange³

1989

Proc. Natl. Acad. Sci. U.S.A.

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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 is >73% identical with that of a neutral (pI 6.7) detoxification enzyme, glutathione transferase P from rat hepatoceliular carcinoma ( Previous reports characterized a metabolic pathway for ethanol in extrahepatic organs (1, 2) that we now relate to an important pathway for metabolism of carcinogens in liver. Brain, heart, and other organs lack oxidative ethanol metabolism and yet they are often injured by alcohol abuse. The observation that fatty acid ethyl esters (FAEEs) are synthesized at high rates in these tissues provided a plausible link between the observed tissue damage and the ingestion of alcohol (2). Moreover, these neutral lipids are potentially toxic for mitochondria (3) and, therefore, FAEEs may account in part for extrahepatic patterns of selective end-organ damage due to alcohol abuse. Recent genetic studies using human peripheral leukocytes have shown that this synthase activity is heritable in an autosomal recessive pattern for high activity (4,5).We have purified both a minor (cationic) and a major (anionic) form of FAEE synthase from human myocardium (6). The anionic form of FAEE synthase has a molecular weight of 26,000 and is the counterpart of that from rabbit heart (1). With these purified preparations, free fatty acid was found to be the lipid substrate precursor, and the driving force for the reaction was shown to be a large increase in AS* (7-10). Despite these recent advances in characterizing the reaction and the protein, the relationship of FAEE synthase to any known family of proteins has escaped definition. Our current work not only relates this enzymatic system to detoxification pathways for xenobiotics/carcinogens but also points out its importance to alcohol metabolism in the liver and to cytochrome P450 metabolism of ethanol and carcinogens.

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The Effect of Chronic Alcohol Intake Upon the Hepatic Microsomal Carcinogen-activation System

Cited by 31 publications

References 8 publications

Identification of a satellite fatty acid ethyl ester synthase from human myocardium as a glutathione S-transferase.

Identification of a satellite fatty acid ethyl ester synthase from human myocardium as a glutathione S-transferase.

The Effect of Chronic Ethanol Intake on the Growth and Spread of Some Murine Tumors

Metabolism of ethanol and carcinogens by glutathione transferases.

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