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E C McCoy

Publications and source records attributed to E C McCoy.

At least 19 recordsLinked to original sources
PubMed1999

Differential antimutagenicity of WR-1065 added after irradiation in L5178Y cell lines.

The purpose of this study was to determine the antimutagenicity of WR-1065 added after irradiation of cells of cell lines differing in their ability to rejoin radiation-induced DNA double-strand breaks (DSBs). The postirradiation antimutagenicity of WR-1065 at the thymidine kinase locus was demonstrated for L5178Y (LY)-S1 cells that are deficient in repair of DNA DSBs. Less postirradiation antimutagenicity of WR-1065 was observed in LY-R16 and LY-SR1 cells, which are relatively efficient in DSB repair. Postirradiation treatment with WR-1065 had only a small stimulatory effect on DSB rejoining. A 3-h incubation of irradiated LY cells with WR-1065 caused slight changes in the distribution of cells in the phases of the cell cycle that differed between LY-S1 and LY-SR1 cells. Both LY-S1 and LY-SR1 cells were protected against the cytotoxic and mutagenic effects of radiation when WR-1065 was present 30 min before and during the irradiation. We conclude that the differential postirradiation effects of WR-1065 in the LY-S1 and LY-SR1 cells are not caused by differences in cellular uptake of the radioprotector or in its radical scavenging activity. Possible mechanisms for the postirradiation antimutagenicity of WR-1065 are discussed.

Animals↗
PubMed1994

Pathways for the mutagenesis of 1-nitropyrene and dinitropyrenes in the human hepatoma cell line HepG2.

The mutagenicity, metabolism, DNA adduction and induction of unscheduled DNA synthesis (UDS) of 1-nitropyrene and 1,8-dinitropyrene were investigated in the human hepatoma cell line HepG2. Previous results had demonstrated that 1-nitropyrene was both mutagenic at the hgprt locus and induced UDS in these cells. In the present study, we find that the dinitropyrenes, although highly mutagenic in Salmonella typhimurium, are not mutagenic and do not induce UDS in the HepG2. Although the rate of 1,8-dinitropyrene nitroreduction was less than that of 1-nitropyrene nitroreduction, this did not explain the lack of mutagenicity and UDS induction by the dinitropyrenes. Therefore, it is proposed that the arylhydroxylamine O-esterificase is not expressed in these cells. Since cytochrome P450-mediated C-oxidation is the predominant metabolic pathway in vivo, we sought to determine if an increase in the ratio of cytochrome P450-mediated C-oxidation over nitroreduction would result in increased or decreased DNA adducts in the HepG2. The administration of 2.5 microM 3-methylcholanthrene to the HepG2 increased the ratio of C-oxidation/nitroreduction from 2.8 +/- 1.9 to 50.4 +/- 46.1. This was accompanied by a decrease in the C8-guanyl adduct of 1-nitropyrene (via nitroreduction) from 18.7 +/- 7.0 to 4.8 +/- 1.7 fmoles/micrograms DNA, without any further increase in other 1-nitropyrene DNA adducts. These results suggest that the cytochrome P450-mediated metabolism of 1-nitropyrene to epoxides, phenols, and dihydrodiols is not an activation pathway in the HepG2 cells, and may explain the weak carcinogenicity of 1-nitropyrene in vivo, where cytochrome P450-mediated C-oxidation predominates.

Biotransformation↗
PubMed1987

Photochemical instability of 1-nitropyrene, 3-nitrofluoranthene, 1,8-dinitropyrene and their parent polycyclic aromatic hydrocarbons.

The environmental contaminants pyrene, 1-nitropyrene, 1,8-dinitropyrene, fluoranthene, and 3-nitrofluoranthene were exposed to light (greater than or equal to 310 nm) either in DMSO, or following coating onto silica. Under all conditions tested the pyrenyl were less stable than the fluoranthenyl compounds. During irradiation in DMSO or on silica, 1-nitropyrene had half-lives of 1.2 and 6 days, while those of 3-nitrofluoranthene were 12.5 and greater than 20 days, respectively. The photodecomposition of 1,8-dinitropyrene resembled that of 1-nitropyrene with half-lives of 0.7 and 5.7 days. A principle photodecomposition product of 1,8-dinitropyrene was identified as 1-nitropyren-8-ol. It was also found that when the nitroarenes were exposed to light, the loss of compound was associated with a concomitant loss of mutagenicity in Salmonella typhimurium strain TA98. The mechanism of nitrated polycyclic aromatic hydrocarbon decomposition and 1-nitropyren-8-ol formation, and the relevance to the atmospheric disposition of these compounds are discussed.

Dimethyl Sulfoxide↗
PubMed1987

Sequential and differing nitroreductive pathways for mutagenic nitropyrenes in Salmonella typhimurium.

The nitro group of nitropyrenes is required for mutagenicity in Salmonella typhimurium. 1-Nitropyrene and 1,3-dinitropyrene are reduced by the 'classical' nitroreductase, which involves a single electron transfer, while the reduction of the first nitro group of 1,6- and 1,8-dinitropyrene proceeds by a two-electron transfer mechanism and involves a different enzyme. However, reduction of the second nitro group, which is not necessary for the mutagenicity of nitropyrenes but is required for the mutagenicity of aminonitropyrenes, is catalyzed by the 'classical' nitroreductase.

Biotransformation↗
PubMed1986

Mutagenicity of the phenacetin metabolites: N-hydroxy-p-phenetidine and nitrosophenetol in S. typhimurium TA100 and derivatives deficient in nitroreductase or O-acetylase: probes for testing intrabacterial metabolic activation.

Two mutagenic metabolites of phenacetin, p-nitrosophenetol and N-hydroxy-p-phenetidine, were tested in S. typhimurium strains TA100, its nitroreductase-deficient derivative TA100NR, and O-acetylase-deficient strains TA100 Tn5-1,8-DNP1011 and -DNP1012 in the presence or absence of an exogenous metabolic activation system. The results indicate that bacterial nitroreductase(s) and O-acetylase(s), shown to be involved in the conversion of certain nitroarenes, are not required for the intrabacterial activation of the two phenacetin metabolites to bacterial mutagens. In view of the low reactivity of nitrosoarenes towards nucleophiles at neutrality, the mechanism by which they exert such a high mutagenic effect in S. typhimurium strains remains to be clarified, but is discussed.

Acetylesterase↗
PubMed1985

The role of DNA sequence and structure of the electrophile on the mutagenicity of nitroarenes and arylamine derivatives.

The mutagenicities of a series of nitroarenes and related electrophilic metabolites of aromatic amines were studied in Salmonella typhimurium strains TA98 and TA97, which have, respectively, (GCGC/CGCG)2 and (CCC/GGG)2 as their mutational sites. For electrophiles, primarily bicyclic species, that form adducts with nucleophilic sites other than the C8 of guanine (G), the ratios of activities in the two strains is near unity. On the other hand, for electrophiles consisting of cyclic structures with more than two rings and that are reported to react solely with the C8 of G, the ratio of activities (TA98/TA97) is in excess of 1.6. Quantum mechanical calculations indicate that (1) in the plane of G, the N7, N3, and 06 of G are more likely nucleophilic targets than C8 and (2) adduct formation at the C8 of G requires electrophilic attack from above or below the plane of G. It is hypothesized that because of steric hindrances, nitroarenes and derivatives containing in excess of two rings cannot react with the preferred nucleophilic sites and, therefore, form adducts with the more accessible C8. However, such an out-of-the-plane attack is influenced by the nature of the nearest neighbor, as evidenced by the difference in mutagenic responses of TA98 and TA97, alternating GCs being preferred over other combinations. Further quantum mechanical calculations indicate that the nature of the nearest neighbor does indeed affect the nucleophilicity of the C8 of G but that the expression of this effect is apparently masked by the overriding steric effects.

Amines↗
PubMed1985

Genetic and quantum chemical basis of the mutagenicity of nitroarenes for adenine-thymine base pairs.

The mutagenicity of nitroarenes for Salmonella typhimurium strains with adenine-thymine base pairs at the mutational site is dependent upon enzymic reduction of the nitro function. Although the electrophilic metabolites of nitroarenes are capable of mutating adenine-thymine base pairs, they show a marked preference for guanine-cytosine pairs when given a choice. Quantum chemical calculations indicate the reactivity order for nucleophilic sites in an AT run of base pairs to be the N-7 of adenine (N7(A)) first, followed by an approximately equal reactivity for C-8 of adenine (C8(A)) and O4 of thymine (O4(T)). Given the low probability of reaction of electrophilic metabolites of nitroarenes with adenine-thymine base pairs, the mutagenic potency of nitroarenes for strains with adenine-thymine base pairs at the mutational site is remarkable.

Adenine↗
PubMed1985

Carcinogenic N-hydroxylaminopurine derivatives do not act as base analog mutagens in Salmonella typhimurium.

N-Hydroxylaminopurines are highly mutagenic for growing as well as resting Salmonella typhimurium strain TA100 and to a lesser extent for strain TA98. Aminopurines, under similar conditions, are not mutagenic. N-Methylhydroxylaminopurine, under similar conditions, exhibits only minimal activity. The results are taken to indicate that unlike non-hydroxylated aminopurines, N-hydroxylaminopurines exert their mutagenicity not by acting as base analogs but by direct covalent binding with DNA-guanine.

Adenine↗
PubMed1985

Non-mutagenicity of YTR 830 H, a novel beta-lactamase inhibitor.

The Ames test indicated that a novel beta-lactamase inhibitor YTR 830 H, belonging to penicillanic acid sulfone was non-mutagenic for any of the tester strains of Salmonella typhimurium TA 98, TA 100 and TA 102. The test was performed both in the presence and absence of S9 activation mixtures which were prepared from the livers of Aroclor 1254-induced Syrian hamsters.

Mutagenicity Tests↗
PubMed1985

Reaction potentials of the constituent bases of DNA and the effects of base stacking.

Reaction potential maps (RPM's) around the constituent bases of DNA have been plotted using the CNDO/2 method. The maps were drawn to evaluate site selectivity in electrophilic attack on the bases of DNA as a function of two considerations: base sequence and the nature of the attacking reagent. It was found that base sequence does have a substantial effect on a site's reactivity and that a change in the nature of the attacking reagent can alter site selectivity of the electrophile. The former result was applied in a specific case to offer a plausible explanation for some results of a recent study of the mutagenic effects of arylating metabolites of nitrofluorenes in the Salmonella tester strains TA98 and TA97. These strains differ in the arrangement of guanine and cytosine residues at the mutational target ("hot spot"). The results also suggest that the "hot spot" for TA98, which consists of a run of alternating guanine and cytosine base pairs, does not exist in the Z-configuration.

Base Sequence↗
PubMed1984

Non-mutagenicity of KBT-1585, a novel ester of ampicillin.

The Ames test indicated that ampicillin (ABPC) and its novel ester KBT-1585 were non-mutagenic for any of the tester strains of Salmonella typhimurium TA 98, TA 100, TA 1535 and TA 1538, both in the presence and in the absence of rat liver microsomal activation mixtures. Diacetyl, the first metabolite of KBT-1585 by the in vitro hydrolysis proved to be non-mutagenic for a new tester strain TA 102 which is exquisitely sensitive to ketones and aldehydes.

Ampicillin↗
PubMed1983

5-Nitroacenaphthene: a newly recognized role for the nitro function in mutagenicity.

The direct-acting mutagenicity of 5-nitroacenaphthene for Salmonella typhimurium is dependent upon the reduction of the nitro function as evidenced by the significant decrease in mutagenicity seen with nitroreductase-deficient Salmonella strains. Addition of microsomal preparations results in a significant increase in mutagenicity and a by-passing of the block in nitroreductase-deficient and arylhydroxylamine esterifying-deficient enzyme strains. The results are taken to indicate that the microsome-induced mutagenicity is due primarily to oxidation of the acenaphthene moiety. The results are consistent with recent studies which indicate that the nitro function exercises a directing effect on ring oxidation.

Acenaphthenes↗