Quantitative Studies on the in Vitro Metabolic Activation of Dimethylnitrosamine by Rat Liver Postmitochondrial Supernatant

The metabolic activation of dimethylnitrosamine (DMN) to mutagenic and/or cytotoxic intermediates in vitro has been characterized and the relationship between DMN demethylase and ethoxyresorufin-O-deethylase (EROD) or ethylmorphine-N-demethylase (EMND) has been evaluated. A mammalian assay system wh...

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Bibliographic Details
Published in:Environmental health perspectives 1984-08, Vol.57, p.327-332
Main Authors: Doolittle, David J., Goodman, Jay I.
Format: Article
Language:English
Subjects:
Animals
Biotransformation
Cell Line
Cell Survival - drug effects
Cytochrome P-450 CYP1A1
Cytochrome P-450 CYP2E1
Cytochrome P-450 Enzyme System - metabolism
Cytochromes
Cytotoxicity
Dimethylnitrosamine - metabolism
Enzymes
Ethylmorphine-N-Demethylase - metabolism
In Vitro Techniques
Isoenzymes
Liver
Male
Metabolism
Mitochondria, Liver - metabolism
Mutagenicity
Mutagens
Oxidases
Oxidoreductases - metabolism
Oxidoreductases, N-Demethylating - metabolism
Polychlorinated biphenyls
Protein metabolism
Proteins - metabolism
Rats
Rats, Inbred Strains
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Summary:The metabolic activation of dimethylnitrosamine (DMN) to mutagenic and/or cytotoxic intermediates in vitro has been characterized and the relationship between DMN demethylase and ethoxyresorufin-O-deethylase (EROD) or ethylmorphine-N-demethylase (EMND) has been evaluated. A mammalian assay system which uses the postmitochondrial supernatant (S-15 fraction) prepared from a rat liver homogenate as an enzyme source and V79 Chinese hamster cells as targets for chemically induced damage was used. The enzyme pattern of the S-15 fraction was altered by pretreatment of experimental animals in vivo and/or by the use of enzyme inhibitors in vitro. The results of these studies indicate that the concentration of S-15 fraction in the reaction mixture can markedly influence the degree of DMN-induced cytotoxicity when it is metabolized in vitro and that the degree of DMN-induced cytotoxicity and mutagenicity are linearly related. The degree of cytotoxicity and mutagenicity induced in V79 cells by DMN does not correlate with EROD activity (a measure of 3-methylcholanthrene-inducible mixed-function oxidases) nor with EMND activity (a measure of phenobarbital-inducible mixed function oxidases) in the S-15 fraction.
ISSN:0091-6765
1552-9924
DOI:10.1289/ehp.8457327