Cytochrome P450 catalyzed metabolism of 1,2-dibromoethane in liver microsomes of differentially induced rats

Wormhoudt, L.W.; Ploemen, J.P.H.T.M.; Commandeur, Jan N. M.; Ommen, Ben van; Bladeren, P.J. van; Vermeulen, Nico

doi:10.1016/0009-2797(95)03659-8

Cited by 8 publications

(2 citation statements)

References 33 publications

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“…DBA are direct-acting mutagens in bacteria ( − ), although metabolic activation can enhance their biological effects ( − ), and they also induce mutations in Drosophila () and mammalian cells ( − ). The two principal routes of metabolic transformation of DBA in mammalian cells are direct conjugation with reduced glutathione (GSH) and cytochrome P450-mediated oxidation ( − ). In the case of DBE, the GSH conjugation pathway produces a sulfur half-mustard, S -(2-haloethyl)glutathione, which rearranges to a reactive episulfonium anion as the ultimate metabolite ( − ) and is able to produce a variety of adducts in DNA.…”

Section: Introductionmentioning

confidence: 99%

“…While this route represents only 20% of the total metabolism of dihaloalkanes in rats (21), it has been considered of major importance in genotoxicity and tumor formation via such DNA damage (5,(24)(25)(26)(27)(28)(29)(30). The P450-mediated oxidation of DBE (3,17,20,22,23) produces 2-bromoacetaldehyde and 2-bromoethyl alcohol which are also potential DNA-damaging metabolites. By analogy to the reaction of chloroacetaldehyde with polynucleotides, the formation of 1-hydroxy-2-chloroethyl monoadducts with exocyclic nitrogen atoms would be expected (31).…”

Section: Introductionmentioning

confidence: 99%

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Mammalian Cells Expressing Escherichia coli O⁶-Alkylguanine-DNA Alkyltransferases Are Hypersensitive to Dibromoalkanes

Abril

Margison

1999

Chem. Res. Toxicol.

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The effect of expression of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, on the growth inhibitory effects of the dibromoalkanes (DBA) dibromomethane (DBM) and dibromoethane (DBE) was determined in Chinese hamster lung fibroblasts transfected with and expressing high levels of the Escherichia coli alkyltransferase (ATase) genes. These included the ogt gene and complete or truncated versions of the E. coli ada gene encoding either O6-alkylguanine (O6-alkG) or alkylphosphotriester (alkPT) ATase activities. The functional activity of the ATase in these cells was demonstrated by in vitro assay of cell extracts using 3H-methylated DNA as a substrate, and by the protection they provided against the growth inhibitory effects of methylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU) and the chloroethylating agent 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, cells expressing the full length or the O6-alkG ATase region, but not the alkPT ATase region, of Ada were found to be more sensitive to the growth inhibitory effects of the DBA; Ogt expression sensitized cells to DBM but not significantly to DBE. Addition of DBA to cell extracts depleted O6-alkG ATase activity on the methylated DNA substrate, but had no effect on alkPT ATase activity. This suggests that ATase-mediated sensitization of the intact cells may be related to the inactivation of the ATase protein. Addition to the cell culture medium of GSH or buthionine sulfoximine in attempts to augment or deplete cellular levels of GSH had no marked effect on the ATase-mediated sensitization to DBA. This suggests that rather than GSH-mediated DNA damage, the effect may be mediated by a DNA adduct caused by the oxidative metabolic pathway. These observations indicate that expression of ATase may have a detrimental effect on cellular sensitivity to environmentally relevant alkylating agents.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mammalian Cells Expressing Escherichia coli O⁶-Alkylguanine-DNA Alkyltransferases Are Hypersensitive to Dibromoalkanes

Abril

Margison

1999

Chem. Res. Toxicol.

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Inter-individual variability in the oxidation of 1,2-dibromoethane: use of heterologously expressed human cytochrome P450 and human liver microsomes

Wormhoudt¹,

Ploemen

Waziers

et al. 1996

Chemico-Biological Interactions

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Insights into chlorantraniliprole exposure via activating cytochrome P450-mediated xenobiotic metabolism pathway in the Procambarus clarkii: Identification of P450 genes involved in detoxification

Liu,

Bian,

Jiang

et al. 2024

International Journal of Biological Macromolecules

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Cytochrome P450 catalyzed metabolism of 1,2-dibromoethane in liver microsomes of differentially induced rats

Cited by 8 publications

References 33 publications

Mammalian Cells Expressing Escherichia coli O⁶-Alkylguanine-DNA Alkyltransferases Are Hypersensitive to Dibromoalkanes

Mammalian Cells Expressing Escherichia coli O⁶-Alkylguanine-DNA Alkyltransferases Are Hypersensitive to Dibromoalkanes

Inter-individual variability in the oxidation of 1,2-dibromoethane: use of heterologously expressed human cytochrome P450 and human liver microsomes

Insights into chlorantraniliprole exposure via activating cytochrome P450-mediated xenobiotic metabolism pathway in the Procambarus clarkii: Identification of P450 genes involved in detoxification

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Cytochrome P450 catalyzed metabolism of 1,2-dibromoethane in liver microsomes of differentially induced rats

Cited by 8 publications

References 33 publications

Mammalian Cells Expressing Escherichia coli O6-Alkylguanine-DNA Alkyltransferases Are Hypersensitive to Dibromoalkanes

Mammalian Cells Expressing Escherichia coli O6-Alkylguanine-DNA Alkyltransferases Are Hypersensitive to Dibromoalkanes

Inter-individual variability in the oxidation of 1,2-dibromoethane: use of heterologously expressed human cytochrome P450 and human liver microsomes

Insights into chlorantraniliprole exposure via activating cytochrome P450-mediated xenobiotic metabolism pathway in the Procambarus clarkii: Identification of P450 genes involved in detoxification

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Mammalian Cells Expressing Escherichia coli O⁶-Alkylguanine-DNA Alkyltransferases Are Hypersensitive to Dibromoalkanes

Mammalian Cells Expressing Escherichia coli O⁶-Alkylguanine-DNA Alkyltransferases Are Hypersensitive to Dibromoalkanes