Metabolism and mutagenicity of halogenated olefins--a comparison of structure and activity.

Henschler, D.

doi:10.1289/ehp.772161

Cited by 17 publications

(6 citation statements)

References 15 publications

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“…Hydrolysis is dominated by C-C bond scission (Table 1) (17)(18)(19). PCE oxide is more stable than the unsymmetrical epoxides, as previously shown by others (5,13,14). Some Cl -migration does occur, even in the absence of Lewis acids (39).…”

Section: Discussionmentioning

confidence: 56%

“…In light of the attention given to PCE oxide as an oxidation product of PCE (1,2,5,6,8,10,(12)(13)(14)35), we prepared this epoxide and characterized some of its properties and its behavior in several reactions. At 37°C , the t 1/2 in aqueous buffer (pH 7.4) was 2.6 min, compared to the t 1/2 of 11.6 min reported by Kline et al (36).…”

Section: Discussionmentioning

confidence: 99%

“…PCE has been shown to cause hepatocellular carcinomas in mice but not rats (3,4). The mechanism of tumorigenesis is unclear; PCE is not very mutagenic in standard test systems, even in the presence of activating enzymes (5).…”

Section: Introductionmentioning

confidence: 99%

“…Cl 3 CCO 2 H and oxalic acid are the two major oxidation products identified in vivo or in liver microsomal incubations (6,8,10,11). The pathway leading to these products is usually presented with PCE oxide as an obligate intermediate (Scheme 1) (1,5,6,8,10,(12)(13)(14). Evidence has been presented for the formation of N 6 -trichloroacetylLys in proteins following microsomal oxidation of PCE, and the pathway involving PCE oxide (and its hydrolytic opening to Cl 3 CCO 2 H) is the basis of assessments of risk estimated from physiologically based pharmacokinetics and other modeling (15,16).…”

Section: Introductionmentioning

confidence: 99%

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Tetrachloroethylene Oxide: Hydrolytic Products and Reactions with Phosphate and Lysine

Yoshioka

Krauser

Guengerich

2002

Chem. Res. Toxicol.

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Tetrachloroethylene, or perchloroethylene (PCE), has considerable industrial use and is of toxicological interest because of a variety of effects. Most of the existing literature presents PCE oxide as a critical intermediate in the oxidative metabolism of PCE to Cl(3)CCO(2)H, oxalic acid, and products covalently bound to proteins, including trichloroacetyl derivatives of lysine. PCE oxide was synthesized by photochemical oxidation of PCE and characterized. Decomposition at neutral pH (t(1/2) = 7.9 min at 0 degrees C, 5.8 min at 23 degrees C, 2.6 min at 37 degrees C) yielded only trace ( approximately 1%) Cl(3)CCO(2)H; the major products identified were CO (73% yield) and CO(2) (63% yield). In phosphate buffer (0.10 M) a major product was identified as oxalyl phosphate. Oxalyl chloride also reacted to form CO and CO(2) in aqueous solution and to form oxalyl phosphate in neutral phosphate buffer. Oxalyl phosphate decomposed to oxalic acid (t(1/2) = 53 min at 37 degrees C) but did not react with lysine. Reaction of PCE oxide with free lysine yielded the oxalic acid amide derivatives of lysine plus lysine dimers in which cross-linking of the amino groups involved oxalo linkage. The reaction of PCE oxide with albumin yielded mainly N(6)-oxalolysine and some (<5%) N(6)-trichloroacetyllysine. We propose a reaction pathway for PCE oxide based on our previous studies with trichloroethylene oxide, in which C-C bond scission is a major product of reaction in aqueous buffer and yields CO and CO(2). Oxalyl species are proposed as intermediates and prominent acylating species formed in the reactions of the epoxide. The formation of Cl(3)CCO(2)H in cytochrome P450 reactions is postulated to result from intramolecular migration within an enzyme intermediate.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tetrachloroethylene Oxide: Hydrolytic Products and Reactions with Phosphate and Lysine

Yoshioka

Krauser

Guengerich

2002

Chem. Res. Toxicol.

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“…1, 1-DCE is metabolized via oxirane intermediates to chloracetylchloride, which is either detoxified by reaction with glutathione (GSH) or reacts with cellular constituents leading to hepatic cytolethality, increased plasma li ver enzyme levels, and death of the animal if the li ver damage is sufficiently extensi ve (24)(25)(26). With certain of these materials, metabolism of the parent chemical produces in termediates that are much more toxic than the parent chemical itself.…”

Section: L-dichloroethylene( I I-dce)mentioning

confidence: 99%

Biologically Based Pharmacodynamic Models: Tools for Toxicological Research and Risk Assessment

Conolly

Andersen²

1991

Annu. Rev. Pharmacol. Toxicol.

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The cancer model contains extensive biological detail, but is not fully validated. It is extremely useful for organizing what is known about malignant transformation, for linking measures of tissue dose with biological processes, and for proposing new experiments. It became very clear, as the cancer model was developed, that we lack an adequate understanding of the details of biochemical mechanisms of carcinogen action linking the target-tissue dose of carcinogen with effects on cell birth, death, and mutation rates as specified by the MVK model. This problem extends to noncarcinogenic toxicants such as methotrexate and the organophosphates. In these cases the biologically based descriptions of toxicity stop at the first interaction of the chemical with tissue. The linkage from the primary interaction to ultimate toxic effect is a "black box" that, at present, can only be described empirically rather than in biologically based terms. The models for dioxin and prednisolone do illustrate how biological events several steps removed from the initial tissue interaction of the toxicant can be described in quantitative, biologically based terms. As such they point the way for future development of more realistic descriptions in which the use of purely empirical linkages is reduced. Rigorous organization of current knowledge and specification of a logical sequence of new experiments encompass the major reasons for developing biologically based (structural) descriptions of any process. It bears emphasis that biologically based tissue response models, for cancer, for chloroform cytotoxicity, for functional impairment following organophosphate exposure, etc, are in reality quantitative formulations of an hypothesis or proposed mechanism incorporating the pharmacokinetics of the chemical and the linkage between target-tissue dose and toxic effect(s). The quantitative model allows us to see if the hypothesis is consistent with pertinent data and aids in designing experiments to define, refute, or bolster the general nature of the proposed linkages between tissue dose, tissue response and the whole organism's response to the chemical exposure. In this sense these biologically based models are quantitative descriptions of the current level of understanding of toxic effects in animals. We began this review article by looking at the literature on empirical tissue-response models to educate ourselves on the history of PD modeling. We rapidly found that the clear distinction between PK and PD models described in the literature blurs when one moves to biologically based modeling of tissue disposition and tissue response. Many articles on physiologically based pharmacokinetics turn out on close scrutiny to be as closely related to tissue response as they are to kinetics.(ABSTRACT TRUNCATED AT 400 WORDS)

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Induction of rat liver drug-metabolizing enzymes by tetrachloroethylene

Hanioka

Jinno

Toyo’oka

et al. 1995

Arch. Environ. Contam. Toxicol.

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The effect of tetrachloroethylene on Phase I and II drug-metabolizing enzymes in rat liver was examined. Rats were treated orally with tetrachloroethylene daily for five days, at doses of 125, 250, 500, 1,000 and 2,000 mg/kg. The higher doses (> 500 mg/kg) of tetrachloroethylene induced the hepatic microsomal 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase activities associated with the CYP2B subfamily. 7-ethoxyresorufin O-deethylase activity was also induced about 2-fold compared with that of control rats at 500, 1,000, and 2,000 mg/kg dose levels of tetrachloroethylene. However, 7-ethoxycoumarin O-deethylase and 7-methoxyresorufin O-demethylase activities were increased significantly at only the 1,000 mg/kg dose level of tetrachloroethylene (1.4- and 1.5-fold). Although other cytochrome P450-mediated monooxygenase activities such as nitrosodimethylamine N-demethylase, aminopyrine N-demethylase and erythromycin N-demethylase were also induced by tetrachloroethylene, the relative induction to control activity was lower than those of 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase. Western immunoblotting showed that the levels of CYP2B1 and CYP2B2 proteins in liver microsomes were increased at doses of 1,000 and 2,000 mg/kg of tetrachloroethylene. In addition to cytochrome P450-mediated monooxygenases, there was significant induction of the Phase II drug-metabolizing enzymes, DT-diaphorase, glutathione S-transferase activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and UDP-glucuronyltransferase activities towards 4-nitrophenol and 7-hydroxycoumarin. The results indicate that tetrachloroethylene induces both Phase I (CYP2B-mediated monooxygenase) and Phase II drug-metabolizing enzymes (DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase) in the rat liver.

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Metabolism and mutagenicity of halogenated olefins--a comparison of structure and activity.

Cited by 17 publications

References 15 publications

Tetrachloroethylene Oxide: Hydrolytic Products and Reactions with Phosphate and Lysine

Tetrachloroethylene Oxide: Hydrolytic Products and Reactions with Phosphate and Lysine

Biologically Based Pharmacodynamic Models: Tools for Toxicological Research and Risk Assessment

Induction of rat liver drug-metabolizing enzymes by tetrachloroethylene

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