Ethanol hepatotoxicity

There are two isomers of triehloroethane, namely methyl chloroform and 1,1,2-trichloroethane. Animal hepatotoxicity to 1,1,2-trichloroethane is documented in the literature with potentiation of toxieity in association with acetone, isopropyl aleohol and ethanol. Hepatotoxicity, with steatosis, necrosis, elevated serum enzymes, and increased liver weight have been observed in animal models exposed to 1000 ppm of methyl chloroform. Human studies eonsist of ease reports documenting hepatotoxicity, with elevated serum transaminases and fatty liver disease related to 1,1,1-triehloroethane exposure. Epidemiologic evidence suggests little hepatotoxieity related to this agent at exposure levels <350 ppm. ... 

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Okino T, Nakajima T, Nakano M. 1991. Morphological and biochemical analyses of trichloroethylene hepatotoxicity Differences in ethanol- and phenobarbital-pretreated rats. Toxicol Appl Pharmacol 108 379-389. 

Chronic ethanol use increases the risk of hepatotoxicity when acetaminophen is used in high doses however, acute ingestion of alcohol along with an acetaminophen overdose decreases the toxicity of acetaminophen. 

Several animal studies indicate that chloroform interacts with other chemicals within the organism. The lethal and hepatotoxic effects of chloroform were increased by dicophane (DDT) (McLean 1970) and phenobarbital (a long-acting barbiturate) in rats (Ekstrom et al. 1988 McLean 1970 Scholler 1970). Increased hepatotoxic and nephrotoxic effects were observed after interaction with ketonic solvents and ketonic chemicals in rats (Hewitt and Brown 1984 Hewitt et al. 1990) and in mice (Cianflone et al. 1980 Hewitt et al. 1979). The hepatotoxicity of chloroform was also enhanced by co-exposure to carbon tetrachloride in rats (Harris et al. 1982) and by co-exposure to ethanol in mice (Kutob and Plaa 1962). Furthermore, ethanol pretreatment in rats enhanced chloroform-induced hepatotoxicity (Wang et al. 1994) and increased the in vitro metabolism of chloroform (Sato et al. 1981). 

Ikatsu H, Nakajima T. 1992. Hepatotoxic interaction between carbon tetrachloride and chloroform in ethanol treated rats. Arch Toxicol 66(8) 580-586. 

In animal studies acetone has been found to potentiate the toxicity of other solvents by altering their metabolism through induction of microsomal enzymes, particularly cytochrome P-450. Reported effects include enhancement of the ethanol-induced loss of righting reflex in mice by reduction of the elimination rate of ethanol increased hepatotoxicity of compounds such as carbon tetrachloride and trichloroethylene in the rat potentiation of acrylonitrile toxicity by altering the rate at which it is metabolized to cyanide and potentiation of the neurotoxicity of -hexane by altering the toxicokinetics of its 2,4-hexane-dione metabolite.Because occupationally exposed workers are most often exposed to a mixmre of solvents, use of the rule of additivity may underestimate the effect of combined exposures. ... 

Saravanan, N., Rajasankar, S. and Nalini, N. (2007) Antioxidant effect of 2-hydroxy-4-methoxy benzoic acid on ethanol-induced hepatotoxicity in rats. Journal of... 

Haloalkanes. Certain haloalkanes and haloalkane-containing mixtures have been demonstrated to potentiate carbon tetrachloride hepatotoxicity. Pretreatment of rats with trichloroethylene (TCE) enhanced carbon tetrachloride-induced hepatotoxicity, and a mixture of nontoxic doses of TCE and carbon tetrachloride elicited moderate to severe liver injury (Pessayre et al. 1982). The researchers believed that the interaction was mediated by TCE itself rather than its metabolites. TCE can also potentiate hepatic damage produced by low (10 ppm) concentrations of carbon tetrachloride in ethanol pretreated rats (Ikatsu and Nakajima 1992). Acetone was a more potent potentiator of carbon tetrachloride hepatotoxicity than was TCE, and acetone pretreatment also enhanced the hepatotoxic response of rats to a TCE-carbon tetrachloride mixture (Charbonneau et al. 1986). The potentiating action of acetone may involve not only increased metabolic activation of TCE and/or carbon tetrachloride, but also possible alteration of the integrity of organelle membranes. Carbon tetrachloride-induced liver necrosis and lipid peroxidation in the rat has been reported to be potentiated by 1,2- dichloroethane in an interaction that does not involve depletion of reduced liver glutathione, and that is prevented by vitamin E (Aragno et al. 1992). 

Berman E, House DE, Allis JW, et al. 1992. Hepatotoxic interactions of ethanol with allyl alcohol or carbon tetrachloride in rats. J Toxicol Environ Health 37 161-176. 

Kenel MF, Kulkarni AP. 1985a. Ethanol potentiation of carbon tetrachloride hepatotoxicity possible role for the in wVo inhibition of aldehyde dehydrogenase. Gen Pharmacol 16 355-360. 

Tang N. 1987. DDT and ethanol potentiation of the hepatotoxicity of carbon tetrachloride. Chin J Prev Med 21 196-198. 

Hepatotoxic activity. Ethanol (95%) extract of the dried resin, administered intraperitoneally to toads at a dose of 10 mg/ day for 14 days, was active. The results were significant atp < 0.01 leveP h Histamine release stimulation. Water extract of the seed, administered intrader-mally to human adults, was active on human basophils k... 

Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25-50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years. 

Berman, E., House, D.E., Allis, J.W. Simmons, J.E. (1992) Hepatotoxic interactions of ethanol with allyl alcohol or carbon tetrachloride in rats. J. Toxicol, environ. Health, 31, 161-176 Bermudez, E., Mirsalis, J.C. Eales. H.C. (1982) Detection of DNA damage in primary cultures... 

Ikatsu, H., Okino, T. Nakajima, T. (1991) Ethanol and food deprivation induced enhancement of hepatotoxicity in rats given carbon tetrachloride at low concentration. Br. J. ind. Med., 48, 636-642... 

Human CYP2E1 is one of the most efficient P450s to catalyze the oxidation of acetaminophen to NAPQI (157-159). Ethanol and isoniazid cause a time-dependent inhibition and induction of acetaminophen oxidation to NAPQI in humans (160,161) that can decrease risk for hepatotoxicity over the interval of concurrent administration and increase risk for hepatotoxicity a few hours after removal of ethanol or isoniazid. The latter induction phase of CYP2E1 may, in part, be responsible for cases of acetaminophen hepatotoxicity associated with the use of ethanol (162-165) or isoniazid (166-168). However, the induction is modest (2- to 3-fold) therefore, other susceptibility factors, genetic and others such as decreased glutathione stores and nutritional status, are likely to play an important role in some individuals (169-174). 

Thummel KE, Slattery JT, Ro H, et al. Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults. Clin Pharmacol Ther 2000 67 591-599. 

Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. J Am Med Assoc 1994 272 1845-1850. 

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