Mutagenesis metabolism

Z-aminO 1 -methy 1 6 phenylimidazo [4,5-b]-pyridine 2 aminO 3,7,8 trimethylimidazo[4,5 f]quinoxaline 2 aminO 3,4,7,8 tetramethyl 3H imidazO [4,5 f]quinoxaline inoxaline 3 aminO l,4 dimethyl SH pyrid [4,3 b] indole (Trp P I) and 3 aminO l methyl 5H pyrido [4,3 b]indole induced mutagenesis. Metabolic activation was required for positive results b... 

Magee, P.N. in de Serres, F.J., Fouts, J.R., Bend, J.R. and Philpot, R.M. (eds), In Vitro Metabolic Activation in Mutagenesis Testing , Elsevier/North Holland Biomedical Press, Amsterdam, 1976 pp. 213-216. 

The Ames test involves the reversion from a his— to his+ phenotype in any one of multiple bacterial strains (usually five strains are tested simultaneously). If the addition of test compound to a his— strain of bacteria allows them to grow on histidine deficient media, the obvious conclusion is compound-induced mutagenesis and a high potential hazard for the compound being carcinogenic. This test can also be conducted in the presence or absence of metabolic activation, in order to provide more information on potential risks (i.e., the parent compound may not be mutagenic, but the primary metabolite may present a safety risk). In practice, a positive Ames test almost always leads to discontinuing work on a compound of interest, and so these data are always collected prior to nomination of a compound for development. 

While the ddNs and ANPs must be converted intracellularly to their 5 -triphosphates (ddNTPs) or diphosphate derivatives before they can interact as competitive inhibitors/alternate substrates with regard to the natural substrates (dNTPs), the NNRTIs do not need any metabolic conversion to interact, noncompetitively with respect to the dNTPs, at an allosteric, non-substrate binding site of the HIV-1 RT. Through the analysis of NNRTI-resistant mutants, combined with site-directed mutagenesis studies, it has become increasingly clear which amino acid residues are involved in the interaction of the NNRTIs with HIV-1 RT, and, since the conformation of the HIV-1 RT has been resolved at 3.0 A resolution [73], it is now possible to visualize the binding site of the NNRTIs [74],... 

During the last decade, significant advancements in biochemistry, molecular cloning, and random and site-directed mutagenesis, directed evolution of biocatalysts, metabolic engineering and fermentation technology have led us to devise methods to circumvent the disadvantages of whole-cell biotransformation discussed in Section 10.2. The applications of these methods are summarized in this section. 

Beland, F.A. and Kadlubar, F.F. (1990). Metabolic activation and DNA adducts of aromatic amines and nitroaromatic hydrocarbons. In Chemical Carcinogenesis and Mutagenesis, Cooper, C.S. and Grover, P.L. (eds), p. 267. Springer Verlag, Secaucus... 

Primary hepatocyte cultures have been used in vitro to metabolically activate toxins for evaluation with target tissues. Cocultures of rat embryos with hepatocytes have been used to study the role of metabolism in teratogenesis (Oglesby et al., 1986). Lindahl-Kiessling et al., (1989), in an attempt to bring test conditions closer to in vivo conditions, developed an assay utilizing primary rat hepatocytes and human peripheral lymphocytes to detect metabolism-mediated mutagenesis. 

Once isolated, the natural H2 producers can be optimized by conventional mutagenesis, and they should be studied so that we can understand those features that make them the best H2 producers. This characterization would involve the analysis of metabolic fluxes (Stephanopoulos and Sinskey 1993 Schuster et al. 1999) and molecular genetics. It would result in new, previously unknown adaptations necessary for improved H2 production, and could provide information on the most important mutations that are required to obtain excellent H2 producers. Information obtained from these experiments should be used in genetic engineering approaches for optimizing H2 producers. Moreover, excellent H2 producers should be used in bioengineering approaches. 

Dichlorobenzidine is an effective inducer of its own metabolic activation (Iba 1987a). The enhancement of 3,3 -dichlorobenzidine mutagenesis has been associated with the induction of cytochrome P-450d (Iba and Thomas 1988), and may result in the elevation of its carcinogenicity. In other animal studies, 3,3 -dichlorobenzidine was also shown to be a potent inducer of hepatic microsomal enzymic activities mediated by cytochrome-P-448 and P-450 (Iba and Sikka 1983 Iba and Thomas 1988). Consequently, it has been suggested that the hepatocarcinogenicity of 3,3 -dichlorobenzidine may be due, at least in part, to the induction of hepatic cytochrome P-488 and DNA-adduction. 

Commoner, G., Vlthayathll, A. (. and Henry, J. I. Detection of metabolic carcinogen intermediates in urine of carcinogen-fed rats by means of bacterial mutagenesis, Nature (174) 249, 850. 

Three primary tests are incorporated in the health effects area. The microbial mutagenesis assay is based on the property of selected Salmonella typhimurium mutants to revert from a histidine requiring state to prototrophy due to exposre to various classes of mutagens. The test can detect nanogram quantities of mutagens and has been adapted to mimic some mammalian metabolic processes by the addition of a mammalian liver microsomal fraction. The test is used as a primary screen to determine the mutagenic activity of complex mixtures or component fractions. 

Isophorone does not induce gene mutations in bacteria, chromosomal aberrations in vitro, DNA repair in primary rat hepatocytes, or bone marrow micronuclei in mice. Positive effects were observed only in the absence of an exogenous metabolic system in L5178YTK+/— mouse mutagenesis assays as well as in a sister chromatid exchange assay. The weight of evidence of all mutagenicity data supports the contention that isophorone is not a potent DNA-reactive compound. ... 

Mutagenesis Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in 1 of 5 bacterial strains. Oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. 

Mutagenesis Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma/thymidine kinase assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. 

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