In vitro metabolism of methylene chloride in human and animal tissues: Use in physiologically based pharmacokinetic models

Reitz, Richard H.; Mendrala, Alan L.; Guengerich, F. Peter

doi:10.1016/0041-008x(89)90328-1

Cited by 131 publications

(64 citation statements)

References 11 publications

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“…The literature presents conflicting reports on the role of microsomal and cytosolic rodent fractions and GSH in the bioactivation of dihalomethanes (13)(14)(15)(16), and we have been unable to demonstrate a consistent response of CH2Br2-induced base-pair mutations in Salmonella typhimurium tester strains in the presence of GSH or mouse liver cytosol, which would be expected to be considerably more active than rat liver cytosol (7). Enzymes ofthe GSH S-transferase theta class, especially rat GSH S-transferase 5-5, have been shown to be proficient in the conjugation of CH2Cl2 (9).…”

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confidence: 55%

“…The GSH conjugation pathway has been considered relevant to tumor formation, largely because oxidation is a low-Km reaction, whereas both in vitro GSH conjugation and tumorigenesis continue to increase with higher CH2Cl2 levels (10). Rates of GSH conjugation of CH2Cl2 are considerably lower in rats and humans than in mice, and this information-along with physiologically based pharmacokinetic models-has been used to predict that humans, like rats, will be considerably less likely than mice to develop tumors from CH2Cl2 exposure (7,10,11).…”

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confidence: 99%

“…(5) and GSH conjugation (6). The oxidation is catalyzed primarily by cytochrome P450 2E1 (7,8), and the conjugation is catalyzed primarily by GSH S-transferase 5-5 and related theta-class enzymes (9).…”

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Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.

Thier

Taylor

Pemble

et al. 1993

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

179

165

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Dihalomethanes can produce liver tumors in mice but not in rats, and concern exists about the risk of these compounds to humans. Glutathione (GSH) conjugation of dihalomethanes has been considered to be a crifical event in the bioactivation process, and risk assessment is based upon this premise; however, there is little experimental support for this view or information about the basis of genotoxicity. A plasmid vector containing rat GSH S-transferase 5-5 was transfected into the SalmoneUla typhimurium tester strain TA1535, which then produced active enzyme. The transfected bacteria produced base-pair revertants in the presence ofethylene dihalides or dihalomethanes, in the order CH2Br2 > CH2BrCl > CH2CI2. However, revertants were not seen when cells were exposed to GSH, CH2Br2, and an amount of purified GSH S-ransferase 5-5 (20-fold excess in amount of that expressed within the cells). HCHO, which is an end product of the reaction of GSH with dihalomethanes, also did not produce mutations. S-(1-Acetoxymethyl)GSH was prepared as an analog of the putative S-(1-halomethyl)GSH reactive intermediates. This analog did not produce revertants, consistent with the view that activation of dihalomethanes must occur within the bacteria to cause genetic damage, presenting a model to be considered in studies with mammalian cells. S-(1-Acetoxymethyl)GSH reacted with 2'-deoxyguanosine to yield a major adduct, identified as S-[l-(N2-deoxyguanosinyl)methyl]GSH.

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confidence: 55%

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Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.

Thier

Taylor

Pemble

et al. 1993

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

179

165

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“…Development of hepatocellular tumors is thought to be associated with S-chlorome thylglutathione, a putative genotoxic intermediate of DCM, in the GST pathway 16,17) . Because GST activity in the liver is much lower in rats than in mice 18) , DCM might not be a likely cause of hepatocellular tumors in rats. The expression of GST T1-1, which plays the most important role in glutathione conjugation of DCM, is highest in the nucleus of hepatic cells in mice and the nucleus of bile duct epithelial cells in humans 19) .…”

Section: Discussionmentioning

confidence: 99%

Two Offset Printing Workers with Cholangiocarcinoma

Kumagai

2014

Journal of Occupational Health

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“…Examination of hepatic cytosolic fractions prepared from mice, rats, Syrian Golden hamsters and humans show that murine liver possesses a significantly greater capacity to conjugate dichlormethane with GSH than livers from other species 110 . Sherratt et al 111 confimed that mouse GST-T1 had a higher specific activity than the human transferase toward dichlormethane and 1,2-epoxy-3-(4′-nitrophenoxy) propane (1.8-and 16-fold higher, respectively).…”

Section: Interspecies Differences In Gstsmentioning

confidence: 99%