Metabolism of Chemical Carcinogens

Weisburger, John H.; Williams, Gary M.

doi:10.1007/978-1-4613-4449-0_7

Cited by 33 publications

(13 citation statements)

References 159 publications

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“…few examples of chemical carcinogens together with the known or strongly suspected electrophilic, chemically reactive metabolites. This aspect of metabolic activation has been reviewed extensively [161,282] and is also a topic of the other reviews cited in this chapter. A number of compounds like antioxidants, enzyme-inducing or enzymeinhibitory agents have an influence on the activation/inactivation pathways in the metabolism of chemical carcinogens [ 281].…”

Section: Mechanism Of Action Of Organic Carcinogensmentioning

confidence: 99%

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

Lutz

1979

Mutation Research/Reviews in Genetic Toxicology

398

124

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Section: Mechanism Of Action Of Organic Carcinogensmentioning

confidence: 99%

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

Lutz

1979

Mutation Research/Reviews in Genetic Toxicology

398

124

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“…Many chemicals require activation by cellular enzymes (32,33) to become carcinogenic. Ames has been able to surmount this difficulty by using a cell-free activating system coordinate with bacterial reversion analysis (34,35).…”

mentioning

confidence: 99%

Metal-induced infidelity during DNA synthesis.

Sirover¹,

Loeb²

1976

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

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The effect of several divalent cations on the accuracy of DNA replication in vitro has been examined. Only Be2+ altered the accuracy of DNA synthesis using purified DNA polymerase (DNA nucleotidyltransferase; deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase; EC 2.7.7.7) from avian myeloblastosis virus. The Be2+-induced base substitutions occurred with all templates and with all nucleotides tested. Analysis of the product by equilibrium density centrifugation and processive hydrolysis with snake venom phosphodiesterase suggested that the noncomplementary nucleotides were present in phosphodiester linkage. Nearest (AMV), it is possible to quantitate accurately the incorporation of noncomplementary nucleotides, and to determine the reaction parameters that influence base-substitution in vtro. AMV DNA polymerase lacks detectable 3'-5' proof-reading exonuclease activity (7) and thus may not excise a mismatched nucleotide (8-10).The error frequency of AMV DNA polymerase is not influenced by most alterations in the reaction parameters (4,5,7). Accordingly, we have tested exogenous agents to determine their influence on the error frequency. We now report evidence that the treatment of AMV DNA polymerase by beryllium, a carcinogenic metal, increases base substitutions during polynucleotide replication. Modification of AMY DNA polymerase by beryllium is completely reversible, resulting in the restoration of the initial error frequency of the polymerase.MATERIALS AND METHODS Materials. Unlabeled deoxynucleotides were purchased from Calbiochem. Tritium-labeled nucleotides were purchased from New England Nuclear or from Amersham-Searle; 32P-labeled nucleotides were obtained from New England Nuclear.Poly[d(A-T)] was prepared by a de novo catalyzed reaction using Escherichia coli DNA polymerase I (11). All other synthetic polynucleotide templates were purchased from P. L.

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“…A second reason for negative results is a deficiency in activation. Many carcinogen's are known to be species-selective because of differences in metabolism (Weisburger and Williams 1982). Also, certain types of carcinogens such as glycones, complex azo dyes containing benzidine congeners and nitro-aromatics, require a step of bacterial metabolism.…”

Section: Resultsmentioning

confidence: 99%

DNA damage and repair tests for the detection of genotoxic agents

Williams

1984

Food Additives & Contaminants

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In vitro tests for DNA reactivity of chemicals serve several important purposes. Genotoxins can cause toxicity, teratogenicity, mutagenicity and carcinogenicity. Positive results in reliable tests are highly predictive of potential carcinogenicity. Among available tests the hepatocyte primary culture/DNA repair test, including its modifications to provide multispecies and bacterial metabolism, has been demonstrated to be a very sensitive test. Assessment of DNA reactivity of known carcinogens also provides information on their possible mechanisms of action.

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Metabolism of Chemical Carcinogens

Cited by 33 publications

References 159 publications

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis

Metal-induced infidelity during DNA synthesis.

DNA damage and repair tests for the detection of genotoxic agents

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