The pharmacokinetics and macromolecular interactions of perchloroethylene in mice and rats as related to oncogenicity

Schumann, A.M.; Quast, J.F.; Watanabe, P.G.

doi:10.1016/0041-008x(80)90082-4

Cited by 113 publications

(37 citation statements)

References 18 publications

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“…Tetra was not mutagenic in bacteria after metabolic activation by liver subcellular fractions. Radioactivity could not be detected in liver DNA of mice treated with high doses of I4C-tetra (9).…”

Section: Introductioncontrasting

confidence: 49%

“…Tetra, however, is not mutagenic under conditions permitting oxidative metabolism, which suggests that the electrophiles formed either are too short-lived to react with DNA or are rapidly deactivated (11) by reaction with microsomal phospholipids near the site of their metabolic formation within the endoplasmatic reticulum. The lack of mutagenicity of tetra under conditions permitting oxidative metabolism as well as the lack of detectable DNA interactions with tetra in rat and mouse liver (9) suggest that the weak hepatocarcinogenicity of tetra in mice is not due to genotoxic mechanisms. Peroxisome proliferation by the tetra metabolite trichloroacetic acid or an enhanced chronic toxicity of tetra in mice due to higher rates of oxidative metabolism compared to rats may be involved in tetra-induced hepatocarcinogenicity in mice Conjugation of tetra with glutathione is catalyzed by microsomal and cytosolic GSH S-transferases and yields TCVG.…”

Section: Mutagenicity Of Tetra Metabolites In Bilementioning

confidence: 92%

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Mutagenicity of tetrachloroethene in the ames test—metabolic activation by conjugation with glutathione

Vamvakas

Herkenhoff

Dekant

et al. 1989

J. Biochem. Toxicol.

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The mutagenicity of tetrachloroethene (tetra) and its S conjugate, S-(1,2,2-trichlorovinyl)glutathione (TCVG) was investigated using a modified Ames preincubation assay. TCVG was a potent mutagen in presence of rat kidney particulate fractions containing high concentrations of gamma-glutamyl transpeptidase (GGT) and dipeptidases. Purified tetra was not mutagenic without exogenous metabolic activation or under conditions favoring oxidative metabolism. Preincubation of tetra with purified rat liver glutathione (GSH) S-transferases in presence of GSH and rat kidney fractions resulted in a time-dependent formation of TCVG as determined by (HPLC) analysis and in an unequivocal mutagenic response in the Ames test. Experiments with tetra in the isolated perfused rat liver demonstrated TCVG formation and its excretion with the bile; bile collected after the addition of tetra to the isolated perfused liver was unequivocally mutagenic in bacteria in the presence of kidney particulate fractions. The mutagenicity was reduced in all cases by the GGT inhibitor serine borate or the beta-lyase inhibitor aminooxyacetic acid. These results support the suggestion that cleavage of the GSH S conjugate formed from tetra by the enzymes of the mercapturic acid pathway and by beta-lyase may be involved in the nephrocarcinogenic effects of this haloalkene in rats.

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Section: Introductioncontrasting

confidence: 49%

Section: Mutagenicity Of Tetra Metabolites In Bilementioning

confidence: 92%

Mutagenicity of tetrachloroethene in the ames test—metabolic activation by conjugation with glutathione

Vamvakas

Herkenhoff

Dekant

et al. 1989

J. Biochem. Toxicol.

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“…For several other compounds of this type, macromolecular binding, including to DNA, has been demonstrated in vitro (Van Duuren and Banerjee, 1976;Bolt and Filser, 1977;Laib et al, 1979;DiRenzo et al, 1982;MacDonald et al, 1982;Stott et al, 1982;Parchman and Magee, 1982;Miller and Guengerich, 1983). However, DNA binding of chlorinated ethanes and ethylenes other than monochloroethylene and l, !-dichloroethylene has been nonexistent or of a very low order (Schumann et al, 1980;Stott et al, 1982), and specific adducts have not been identified (Parchmann and Magee, 1982;Stott et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…Uehleke and Tabarelli-Poplawski (1977) found protein in binding in vivo and in vitro. Bergman (1983) reported that mouse microsomes in vitro mediated formation of the 1,NO-ethenoadenine adduct in DNA from trichloroethylene, but clear evidence of formation of DNA adducts in vivo was found by Stott et al (198 l) with trichloroethylene or by Schumann et al (1980) with tetrachloroethylene. Nevertheless, to investigate the possibility of species differences in biotransformation, studies in mouse hepatocytes are being done.…”

Section: Discussionmentioning

confidence: 99%

Activities of chlorinated ethane and ethylene compounds in the Salmonella/rat microsome mutagenesis and rat hepatocyte/DNA repair assays under vapor phase exposure conditions

et al. 1985

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Three chlorinated ethane and ethylene solvent products were examined for their genotoxicity in the Salmonella/microsome mutagenesis and hepatocyte primary culture DNA repair assays using vapor phase exposures. The positive control in this study, monochloroethylene (vinyl chloride), induced reversion mutation of Salmonella tester strains TA100 and TA1535 with enhancement by an exogenous activation system and elicited unscheduled DNA synthesis in rat hepatocytes in culture. Exposures to 1,1,1-trichloroethane (methyl chloroform) or 1,1,2-trichloroethylene samples which contained stabilizers resulted in increased recovery of revertant colonies of Salmonella at concentrations causing greater than 96% cell killing. However, these stabilized materials did not induce DNA repair and low-stabilized trichloroethylene did not induce reversion mutation or DNA repair. Exposure of Salmonella tester strains and hepatocytes to highly toxic vapor concentrations of technical grade 1,1,2,2-tetrochloroethylene, low-stabilized and stabilized, increased reversion mutation and elicited DNA repair. Tetrachloroethylene of high purity was not genotoxic. With all of these test products, the presence of an Aroclor-induced rat liver subcellular enzyme preparation in the mutagenesis assay did not have any effect on the results. These observations suggest that stabilizers or unknown impurities normally present at low concentrations in these products are responsible for the positive responses observed at the high exposure concentrations achievable under in vitro test conditions.

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“…Due to its high lipophilicity, perc has been found to distribute widely to all tissues in the body as observed in early lifestages of humans (Gaillard et al, 1995;Garnier et al, 1996;Kö ppel et al, 1985) and early lifestages of animals (Dallas et al, 1994;Ghantous et al, 1986;Savolainen et al, 1977;Schumann et al, 1980;Szakmáry et al, 1997), although this is true for adults as well. It should be noted that the total body burden of perc increases with age (Clewell et al 2004), as would be expected, given that adult body weight is generally positively correlated with age.…”

Section: Distributionmentioning

confidence: 92%

Early lifestage exposure and potential developmental susceptibility to tetrachloroethylene

Dzubow

Makris

Scott

et al. 2009

Birth Defects Research Pt B

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The limited evidence on early lifestage exposure to perc does not provide sufficient evidence of this sensitive period as being more or less important than exposure at a later lifestage, such as during adulthood. However, there are a number of adverse health effects observed uniquely in early lifestages, and increased sensitivity to visual system deficits is suggested in children. Other outcomes observed in adults may not have been adequately assessed in children to directly compare sensitivity.

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The pharmacokinetics and macromolecular interactions of perchloroethylene in mice and rats as related to oncogenicity

Cited by 113 publications

References 18 publications

Mutagenicity of tetrachloroethene in the ames test—metabolic activation by conjugation with glutathione

Mutagenicity of tetrachloroethene in the ames test—metabolic activation by conjugation with glutathione

Activities of chlorinated ethane and ethylene compounds in the Salmonella/rat microsome mutagenesis and rat hepatocyte/DNA repair assays under vapor phase exposure conditions

Early lifestage exposure and potential developmental susceptibility to tetrachloroethylene

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