Biochemical, histological, and ultrastructural changes in rat and mouse liver following the administration of trichloroethylene: Possible relevance to species differences in hepatocarcinogenicity

Elcombe, Clifford R.; Rose, Michael S.; Pratt, Iona

doi:10.1016/0041-008x(85)90135-8

Cited by 109 publications

(37 citation statements)

References 31 publications

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“…Similarly, a direct correlation for peroxisome proliferation and carcinogenic effects of trichloroethylene has also been shown. Trichloroethylene, which is carcinogenic in mice but not in rats was shown to be a peroxisome proliferator in mice; but not in rats (National Toxicology Program, 1983;Elcombe et al, 1985). The results of these different experiments further support the hypothesis that hepatocarcinogenicity of hypolipidaemic compounds is dependent on their biological activity of peroxisome proliferation .…”

Section: Discussionsupporting

confidence: 73%

“…It has been proposed by Reddy and coworkers that the hepatocarcinogenicity of peroxisome proliferators is due to the oxidative stress generated by disproportionate increase of peroxisomal enzymes (Reddy et al, 1982b;Reddy & Rao, 1986;. This hypothesis is supported by the observations that hepatocarcinogenic potency of these compounds is dependent on their ability to induce peroxisome proliferation Elcombe et al, 1985;Tomaszewski et al, 1986).…”

supporting

confidence: 74%

“…Peroxisome proliferation is a unique phenomenon common to several structurally diverse chemicals including hypolipidaemic drugs, phthalate ester plasticizers, industrial solvents and tetrazole substituted alkoxyacetophenone (Hess et al, 1965;Reddy & Krishnakantha, 1975;Moody & Reddy, 1978;Elcombe et al, 1985;Eacho et al, 1986). Of these chemicals, the biological effects of hypolipidaemic drugs and phthalate esters have been extensively studied Reddy et al, 1982a;Cohen & Grasso, 1981;Lake et al, 1984;Reddy & Rao, 1986;.…”

mentioning

confidence: 99%

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Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

Rao

Dwivedi²,

Subbarao³

et al. 1988

Br J Cancer

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Summary The hepatic effects of ciprofibrate, a potent peroxisome proliferator, were evaluated in male C57BL/6N mice, a mouse strain with very low incidence of spontaneous liver tumour development. Dietary feeding of ciprofibrate (0.0125% or 0.025% w/w) for 2 weeks resulted in a marked proliferation of peroxisomes (9-fold increase) and several-fold increase (8-to 10-fold) in the activity of peroxisomal /3-oxidation enzymes. Feeding ciprofibrate at 0.025% concentration for 15 months followed by a 0.0125% for 6 months led to the development of hepatic adenomas in 8/14 (57%) and hepatocellular carcinomas (HCC) in 3/14 (21%) mice. In mice given 0.0125% ciprofibrate for 18 months 5 of 8 (62%) and 3 of 8 (37%) developed adenomas and HCC respectively. Similar to the findings observed in rats, both the adenomas and HCC were negative for y-glutamyltranspeptidase. These results in C57BL/6N mice of hepatocarcinogenic effect of ciprofibrate, a non-genotoxic chemical, indicate that peroxisome proliferation can be used as a reliable parameter to evaluate the carcinogenicity of hypolipidaemic compounds.

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Section: Discussionsupporting

confidence: 73%

supporting

confidence: 74%

mentioning

confidence: 99%

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Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

Rao

Dwivedi²,

Subbarao³

et al. 1988

Br J Cancer

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“…Drug and chemically induced liver enlargement in subchronic and chronic toxicology studies in rodents has, for many years, taxed the toxicology profession in terms of its perceived relevance to hepatotoxicity, to carcinogenicity in lifetime bioassays at similar dose levels, and in terms of its relevance to man (Cohen and Grasso 1981;Elcombe, Rose, and Pratt 1985;Grasso and Hinton 1991). The fact that after more than 50 years of debate (Gilbert and Golberg 1965;Rowe et al 1959;Weil and McCollister 1963) the issue remains as contentious as ever prompted the European Society of Toxicologic Pathology (ESTP) to convene an expert opinion group to discuss the current state of the science.…”

Section: Introductionmentioning

confidence: 99%

Liver Hypertrophy

Elcombe²,

et al. 2012

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Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARa. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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“…DCA is one of the most prevalent haloacetates found in samples from these sources and has been implicated as a toxin to plants and trees at atmospheric exposure levels (Hoekstra et al, 1999;Rompp et al, 2001). DCA is also a by-product of drinking water disinfection (Krasner et al, 1989;Mughal, 1992) and a metabolite of two widely used chlorinated industrial solvents, trichloroethylene and tetrachloroethylene (Coleman et al, 1976;Westrick et al, 1984;Elcombe et al, 1985;Odum et al, 1988) and of certain drugs . Humans may be exposed to DCA by chlorination of municipal drinking water or by groundwater contamination at certain Superfund sites.…”

mentioning

confidence: 99%

Inhibition and Recovery of Rat Hepatic Glutathione S-Transferase Zeta and Alteration of Tyrosine Metabolism Following Dichloroacetate Exposure and Withdrawal

Xu¹,

Dixit²,

Liu³

et al. 2006

Drug Metabolism and Disposition

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ABSTRACT:Dichloroacetate (DCA) is an investigational drug for certain metabolic disorders, a by-product of water chlorination and a metabolite of certain industrial solvents and drugs. DCA is biotransformed to glyoxylate by glutathione S-transferase zeta (GSTz1-1), which is identical to maleylacetoacetate isomerase, an enzyme of tyrosine catabolism. Clinically relevant doses of DCA (mg/kg/day) decrease the activity and expression of GSTz1-1, which alters tyrosine metabolism and may cause hepatic and neurological toxicity. The effect of environmental DCA doses (g/kg/day) on tyrosine metabolism and GSTz1-1 is unknown, as is the time course of recovery from perturbation following subchronic DCA administration. Male Sprague-Dawley rats (200 g) were exposed to 0 g, 2.5 g, 250 g, or 50 mg DCA/kg/day in drinking water for up to 12 weeks. Recovery was followed after the 8-week exposure. GSTz specific activity and protein expression (Western immunoblotting) were decreased in a dose-dependent manner by 12 weeks of exposure. Enzyme activity and expression decreased 95% after a 1-week administration of high-dose DCA. Eight weeks after cessation of high-dose DCA, GSTz activity had returned to control levels. At the 2.5 or 250 g/kg/day doses, enzyme activity also decreased after 8 weeks' exposure and returned to control levels 1 week after DCA was withdrawn. Urinary excretion of the tyrosine catabolite maleylacetone increased from undetectable amounts in control rats to 60 to 75 g/kg/24 h in animals exposed to 50 mg/kg/day DCA. The liver/body weight ratio increased in the high-dose group after 8 weeks of DCA. These studies demonstrate that short-term administration of DCA inhibits rat liver GSTz across the wide concentration range to which humans are exposed.

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Biochemical, histological, and ultrastructural changes in rat and mouse liver following the administration of trichloroethylene: Possible relevance to species differences in hepatocarcinogenicity

Cited by 109 publications

References 31 publications

Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

Induction of peroxisome proliferation and hepatic tumours in C57BL/6N mice by ciprofibrate, a hypolipidaemic compound

Liver Hypertrophy

Inhibition and Recovery of Rat Hepatic Glutathione S-Transferase Zeta and Alteration of Tyrosine Metabolism Following Dichloroacetate Exposure and Withdrawal

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