Ethanol induction of acetaminophen toxicity and metabolism

Peterson, Francis J.; Holloway, David E.; Erickson, Richard R.; Duquette, Peter H.; McClain, Craig J.; Holtzman, Jordan L.

doi:10.1016/0024-3205(80)90646-3

Cited by 68 publications

(28 citation statements)

References 15 publications

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“…4). Levels of 400 mg of acetaminophen/kg producing toxicity in wild-type mice in this study were similar to those that produced toxicity in other studies (20,23). Cyp2e1…”

Section: Production and Characterization Of The Cyp2e1supporting

confidence: 73%

See 1 more Smart Citation

Role of CYP2E1 in the Hepatotoxicity of Acetaminophen

Lee¹,

Buters

Pineau³

et al. 1996

Journal of Biological Chemistry

598

381

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CYP2E1, a cytochrome P-450 that is well conserved across mammalian species, metabolizes ethanol and many low molecular weight toxins and cancer suspect agents. The cyp2e1 gene was isolated, and a mouse line that lacks expression of CYP2E1 was generated by homologous recombination in embryonic stem cells. Animals deficient in expression of the enzyme were fertile, developed normally, and exhibited no obvious phenotypic abnormalities, thus indicating that CYP2E1 has no critical role in mammalian development and physiology in the absence of external stimuli. When cyp2e1 knockout mice were challenged with the common analgesic acetaminophen, they were found to be considerably less sensitive to its hepatotoxic effects than wild-type animals, indicating that this P-450 is the principal enzyme responsible for the metabolic conversion of the drug to its active hepatotoxic metabolite.Cytochromes P-450 (P-450) 1 are a superfamily of hemoproteins that carry out oxidative metabolism of many endogenous and foreign chemicals (1). In mammals, P-450s can be functionally segregated into two groups, those that participate in biochemical pathways leading to the synthesis of steroid hormones and those that primarily metabolize foreign chemicals or xenobiotics such as drugs. The latter enzymes are included in the CYP1, CYP2, CYP3, and CYP4 families (2). Many of the hepatic xenobiotic-metabolizing P-450s also metabolize endogenous compounds, but the significance of these reactions is questionable. A clue to the lack of a critical role for many of the P-450s, particularly those in family 2, in development, reproduction, and longevity, is the marked species differences in their expression and catalytic activities (3). However, some of the xenobiotic-metabolizing P-450s are well conserved, including those in the CYP1 family and CYP2E1, suggesting that they may perform an important physiological function.CYP2E1 is the principal P-450 responsible for the metabolism of ethanol and is considered as a major component of the microsomal ethanol-oxidizing system (4, 5). Among xenobiotics metabolized by CYP2E1 are acetaldehyde, acetaminophen, acrylamide, aniline, benzene, butanol, carbon tetrachloride, diethylether, dimethyl sulfoxide, ethyl carbamate, ethylene chloride, halothane, glycerol, ethylene glycol, N-nitrosodimethylamine, 4-nitrophenol, pyrazole, pyridine, and vinyl chloride (6). Many of these chemicals are known toxins, established chemical carcinogens, or suspected carcinogens. CYP2E1-mediated oxidation of a variety of substrates is also believed to liberate a substantial amount of reactive oxygen that can lead to membrane lipid peroxidation and cell toxicity (7).CYP2E1 is also capable of metabolizing endogenous chemicals including acetone and acetol, which are key metabolites in the methylglyoxal and propanediol pathways of gluconeogenesis (8, 9). CYP2E1 can also carry out the metabolism of arachidonic acid, resulting in the production of several hydroxyeicosatetraenoic acids (10), some of which may have physiological and pharmacol...

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“…4). Levels of 400 mg of acetaminophen/kg producing toxicity in wild-type mice in this study were similar to those that produced toxicity in other studies (20,23). Cyp2e1…”

Section: Production and Characterization Of The Cyp2e1supporting

confidence: 73%

“…Ethanol was reported to increase the toxicity of acetaminophen in mice (20,23), thus suggesting the involvement of CYP2E1 in vivo. In vitro studies have also implicated human CYP1A2 in addition to CYP2E1 in acetaminophen metabolism, although the latter P-450 had a lower K m than CYP1A2 (24,25).…”

mentioning

confidence: 99%

Role of CYP2E1 in the Hepatotoxicity of Acetaminophen

Lee¹,

Buters

Pineau³

et al. 1996

Journal of Biological Chemistry

598

381

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“…Yang et al (21) examined the dealkylation of a series of nitrosamines by the purified cytochromes and showed that P-450 form 3a is the most active toward N-nitrosodimethylamine and is the "low Ki" form of the cytochrome responsible for the activation of this substrate in microsomes. As another example, acetaminophen, a widely used antipyretic and analgesic drug, is normally nontoxic, but in large doses or after chronic exposure of animals and humans to ethanol produces acute hepatic necrosis (22,23). In this case, P-450 form 3a proved to be more active than isozymes 2, 3b, 3c, and 6 (but not isozyme 4) in converting the drug to the reactive intermediate that is capable ofconjugating with glutathione in the reconstituted enzyme system (11).…”

Section: Resultsmentioning

confidence: 99%

Reductive beta-scission of the hydroperoxides of fatty acids and xenobiotics: role of alcohol-inducible cytochrome P-450.

Vaz

Roberts

Coon

1990

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

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As shown previously in this laboratory, purifled rabbit liver microsomal cytochrome P.450 form 2 (P-450 11B4) catalyzes the reductive cleavage of hydroperoxides to yield hydrocarbons and either aldehydes or ketones. We have proposed that lipid hydroperoxides are the physiological substrates for the cleavage reaction and have shown that with 13-hydroperoxy-9,11-octadecadienoic acid the formation of pentane is roughly equimolar with respect to the NADPH consumed. In the present study, the other product was isolated and identified as 13-oxo-9,11-tridecadienoic acid. Ofparticular interest, the alcohol-inducible form of liver microsomal cytochrome P-450 form 3a (P-450 IIE1) is the most active of the isozymes examined in the reductive P-scission of the 13-hydroperoxide derived from linoleic acid and the 15-hydroperoxide derived from arachidonic acid as well as the model compounds cumyl hydroperoxide (a,a-dimethylbenzyl hydroperoxide) and t-butyl hydroperoxide. In general, the forms of P-450 with lower activity, as judged by the rate of NADPH oxidation in the reconstituted system, give less of the cleavage products (hydrocarbon and oxo compound) and catalyze direct reduction of the hydroperoxides to the corresponding hydroxy compounds. The occurrence of the reductive cleavage reaction in liver microsomal membranes was demonstrated, and microsomes from animals treated with ethanol or acetone (P-450 IEl inducers) or phenobarbital (a P-450 11B4 inducer) were more active than those from untreated animals. We suggest that the alcohol-inducible P-450, in addition to its known deleterious effects in chemical toxicity and chemical carcinogenesis, may enhance the reductive cleavage of lipid hydroperoxides with a resultant loss in membrane integrity.Many reactions are known in which the cytochrome P-450 enzyme system catalyzes the hydroxylation of various naturally occurring as well as foreign compounds in the presence of molecular oxygen and a reduced pyridine nucleotide (1). In addition, peroxy compounds can serve as the oxygen donor in the absence ofa reductant, as shown with liver microsomes (2-4) and with purified P-450 (5). With cumyl hydroperoxide (a,a-dimethylbenzyl hydroperoxide), for example, P-450 functions as a peroxygenase by a mechanism apparently involving homolytic oxygen-oxygen bond cleavage, and cumyl alcohol (a,a-dimethylbenzyl alcohol) and the hydroxylated substrate are the products formed (1,6).This laboratory found that P-450 catalyzes the formation of hydrocarbons from hydroperoxides (7). In a reconstituted system containing purified rabbit liver microsomal P-450 form 2*, NADPH-cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4), and NADPH, cumyl hydroperoxide gives methane and acetophenone, but no cumyl alcohol is formed. Since 13-hydroperoxy-9,11-octadecadienoic acid (13-HOO-C18:2), derived from hinoleic acid, yields pentane under these conditions, we proposed that lipid peroxides may be the physiological substrates for the reductive cleavage reaction we found using xeno...

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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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Ethanol induction of acetaminophen toxicity and metabolism

Cited by 68 publications

References 15 publications

Role of CYP2E1 in the Hepatotoxicity of Acetaminophen

Role of CYP2E1 in the Hepatotoxicity of Acetaminophen

Reductive beta-scission of the hydroperoxides of fatty acids and xenobiotics: role of alcohol-inducible cytochrome P-450.

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.

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