Differences in the potentiation of carbon tetrachloride in rats by ethanol and isopropanol pretreatment

Traiger, George J.; Plaa, Gàbriel L.

doi:10.1016/0041-008x(71)90094-9

Cited by 143 publications

(18 citation statements)

References 8 publications

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“…The induction of P-450 by ethanol is associated with an increase in the metabolism and, in some instances, in the toxicity of many compounds, including N-nitrosodimethylamine (4)(5)(6), acetaminophen (7)(8)(9), aniline (10)(11)(12), ethanol (13), and carbon tetrachloride (14)(15)(16). The treatment of rabbits with ethanol also results in an increase in hepatic microsomal aniline and ethanol hydroxylation, but the specific content of microsomal P-450 is not always significantly increased (17).…”

mentioning

confidence: 99%

Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid.

Koop¹,

Crump²,

Nordblom³

et al. 1985

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

171

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Isozyme 3a of rabbit liver microsomal cytochrome P-450, also termed P-450ALC, was previously isolated in this laboratory from animals administered ethanol or imidazole, and the purified cytochrome was shown to function in the reconstituted system as an oxygenase in catalyzing the oxidation of ethanol and other alcohols. Although liver microsomes from animals treated in various ways exhibit increased alcohol-oxidizing activity, evidence was not available as to whether this was due to enzyme induction or to other factors influencing the activity. Immunochemical quantitation of P-450 isozyme 3a has now been achieved by use of purified antibody to this cytochrome in NaDodSO4/PAGE/blotting and dot-blotting techniques. The specific content of isozyme 3a in liver microsomes was found to be increased from 2-to >4-fold by administration of the following agents, in increasing order of effectiveness as inducers: isoniazid, trichloroethylene, pyrazole, ethanol, imidazole, and acetone. Isozyme 3a represents about 5% of the total P-450 in control animals and is increased to as high as 27% by acetone treatment. Isozyme 3a-dependent butanol-oxidation activity, determined by the inhibitory effect of antibody on the various microsomal preparations, was found to increase proportionally with increased content of this cytochrome.Chronic ethanol consumption by rats results in a proliferation of the hepatic smooth endoplasmic reticulum and an increase in NADPH-cytochrome P-450 reductase and spectrally observable cytochrome P-450 (1-3). The induction of P-450 by ethanol is associated with an increase in the metabolism and, in some instances, in the toxicity of many compounds, including N-nitrosodimethylamine (4-6), acetaminophen (7-9), aniline (10-12), ethanol (13), and carbon tetrachloride (14-16). The treatment of rabbits with ethanol also results in an increase in hepatic microsomal aniline and ethanol hydroxylation, but the specific content of microsomal P-450 is not always significantly increased (17). Several years ago in this laboratory, a unique form of P-450, designated isozyme 3a on the basis of its relative electrophoretic mobility, was isolated from ethanol-treated rabbits and characterized (17, 18). More recently, we have purified the same cytochrome from rabbits treated with imidazole (19). Purified isozyme 3a, also referred to as P-450ALC (20), exhibits the highest activity of six purified rabbit liver isozymes toward ethanol and other alcohols as well as aniline (18), converts acetaminophen to a reactive intermediate (21), and is the only P-450 isozyme we have studied that is active in the demethylation of N-nitrosodimethylamine at low substrate concentrations (22). Isozyme 3a is responsible for the increase in oxidation of alcohols and aniline in liver microsomes from ethanol-treated rabbits, as indicated by inhibition of the induced activity with antibody prepared to the purified enzyme (23). Furthermore, the microsomal demethylation of N-nitrosodimethylamine at low substrate concentrations is completely inhi...

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mentioning

confidence: 99%

Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid.

Koop¹,

Crump²,

Nordblom³

et al. 1985

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

171

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“…In a recent study with a low level of ethanol, Ray and Mehendale (1990) demonstrated potentiation of carbon tetrachloride hepatotoxicity by an acute oral dosage of 10 mmol ethanol/kg (0.58 ml/kg) followed by carbon tetrachloride challenge 18 h later. In time-course studies in which 0.1 ml carbon tetrachloride/kg was administered ip to male Sprague-Dawley rats at varying time intervals following an acute gavage with 7 ml ethanol/kg, maximal hepatotoxicity was observed when 18-24 h separated the two exposures (Traiger and Plaa, 1971). Potentiation of carbon tetrachloride hepatotoxicity was observed when 5 g ethanol/kg by gavage was administered to male SpragueDawley rats, followed 16-18 h later by a 2-h inhalation exposure to carbon tetrachloride; however, when ethanol exposure preceded carbon tetrachloride exposure by 2 h, potentiation of carbon tetrachloride toxicity was not observed Adefuin, 1966,1967).…”

Section: Discussionmentioning

confidence: 97%

Hepatotoxic interactions of ethanol with allyl alcohol or carbon tetrachloride in rats

Berman¹,

House²,

Allis³

et al. 1992

Journal of Toxicology and Environmental Health

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To assess whether potential toxic interactions occur between ethanol and allyl alcohol or carbon tetrachloride following subacute, concurrent chemical exposure, male Fischer 344 rats, approximately 70 d of age, were given ethanol at 0, 0.05, 0.1, 0.2, or 0.5 ml/kg in corn oil daily by gavage for 14 d (ETOH group), or the same levels of ethanol with 21 mg allyl alcohol/kg (ALAC group), or the same levels of ethanol with 20 mg carbon tetrachloride/kg (CCL4 group). Hepatic response was assessed 24 h after the last dose. Interactions were evaluated by comparing the ETOH group with either the ALAC group or the CCL4 group using multivariate analysis of variance procedures. No statistically significant interaction was seen between the ETOH group and the ALAC group at the dosages used. Although an interaction between ethanol and carbon tetrachloride given simultaneously was not statistically significant, a small interactive effect on weight gain from d 0 to termination was apparent (p = .057). Exposure to ethanol alone resulted in a concentration-dependent decrease in absolute and relative liver weight, with a threshold between 0.05 and 0.1 ml/kg. There was no histopathological evidence of hepatic damage with ethanol alone, and no effect on hepatic cytochrome P-450 and glutathione levels or on serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALK). Exposure to allyl alcohol alone resulted in significant increases in absolute and relative liver weights, liver glutathione, and periportal hepatocellular vacuolar degeneration. Exposure to carbon tetrachloride alone resulted in significant increases in absolute and relative liver weight, serum levels of ALT, AST, and ALK, and centrilobular hepatocellular vacuolar degeneration and necrosis. These observations indicate that subacute, concurrent exposure of ethanol with carbon tetrachloride or allyl alcohol at ethanol levels comparable to those reported in gavage vehicles did not result in interactive toxicity.

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“…Normal and isobutyl alcohol are metabolized extensively while sec-and tert-butanol are more slowly metabolized and excreted. Traiger and Plaa have further investigated carbon tetrachloride potentiation by isopropyl alcohol (18). These data suggest that in addition to ethanol ingestion, mixed solvent exposures involving other alcohols and halogenated hydrocarbon solvents may be of industrial concern.…”

Section: Alcohols As Potentiators Of Toxicitymentioning

confidence: 99%

“…These data suggest that in addition to ethanol ingestion, mixed solvent exposures involving other alcohols and halogenated hydrocarbon solvents may be of industrial concern. Since in these studies ethanol was given [16][17][18][19][20][21][22][23][24] hr prior to solvent exposure, residual alcohol should be insignificant at the time of solvent exposure. Thus, under such conditions, with ethanol metabolism essentially complete, direct substrate competition is unlikely and other mechanisms must be considered.…”

Section: Alcohols As Potentiators Of Toxicitymentioning

confidence: 99%

Influence of aliphatic alcohols on the hepatic response to halogenated olefins.

Cornish¹,

Barth²,

Ling³

1977

Environ Health Perspect

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The role of alcohols in potentiating the toxicity of halogenated hydrocarbon solvents has been reviewed. The toxicity of carbon tetrachloride and chloroform can be markedly potentiated by prior treatment with ethanol or phenobarbital. Trichloroethylene toxicity may also be potentiated by ethanol ingestion. Prior ethanol ingestion acts by altering biochemical parameters that result in an increased response to subsequent solvent exposure. Simultaneous exposure to both ethanol and trichloroethylene allows for competitive substrate inhibition of metabolism since these compounds share several common enzymatic pathways. Thus the toxic response to multiple exposures varies depending upon the time sequence and the comparative levels of the individual components. Phenobarbital apparently potentiates solvent toxicity by induction of the microsomal mixed function oxidase system. Ethanol, either on a chronic or single dose basis, also has the ability to stimulate this enzyme system. Although alteration of the microsomal mixed function oxidase system by chronic ethanol ingestion may play an important role in potentiation of solvent toxicity, the potentiation seen following a single dose of ethanol cannot be fully accounted for by the known effects of ethanol on the mixed function oxidase system. In addition to ethanol a large number of other alcohols will markedly potentiate the hepatotoxic response to solvents such as carbon tetrachloride and chloroform. The mechanisms involved in such potentiation are not known at the present time.

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Differences in the potentiation of carbon tetrachloride in rats by ethanol and isopropanol pretreatment

Cited by 143 publications

References 8 publications

Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid.

Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid.

Hepatotoxic interactions of ethanol with allyl alcohol or carbon tetrachloride in rats

Influence of aliphatic alcohols on the hepatic response to halogenated olefins.

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