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Biomedical subjects

G D McCoy

Publications and source records attributed to G D McCoy.

At least 37 records · Page 2Linked to original sources
PubMed1981

Differential effect of chronic ethanol consumption on the carcinogenicity of N-nitrosopyrrolidine and N'-nitrosonornicotine in male Syrian golden hamsters.

The effect of chronic ethanol consumption on the carcinogenicity of N'-nitrosopyrrolidine (NPYR) and N'-nitrosonornicotine (NNN) in male Syrian golden hamsters has been investigated. Groups of hamsters were maintained on either ethanol-containing or control liquid diets for 4 weeks prior to and during carcinogen treatment. NPYR or NNN was administered to ethanol-consuming or control hamsters by i.p. injection over a 25-week period in total doses of either 1 or 2 mmol. In the group treated with 1 mmol of NPYR and maintained on a control diet, we observed 1 of 20 hamsters with a nasal cavity tumor and 4 of 20 hamsters with tracheal tumors. In the group treated with 1 mmol of NPYR and maintained on the ethanol-containing diet, we observed 8 of 18 hamsters with nasal cavity tumors and 9 of 18 hamsters with tracheal tumors. The corresponding results in hamsters given 2 mmol of NPYR were: nasal cavity tumors, 14 of 21 (control) and 16 of 17 (ethanol); tracheal tumors, 8 of 21 (control) and 11 of 17 (ethanol). These results demonstrate that the carcinogenicity of NPYR is enhanced in ethanol-treated Syrian golden hamsters, particularly at the lower dose. In the groups treated with 1 mmol of NN and a control diet, we observed 1 of 21 hamsters with a nasal cavity tumor and 4 of 21 with tracheal tumors. In the corresponding ethanol-treated groups, we observed 1 of 17 hamsters with a nasal tumor and 5 of 17 with tracheal tumors. In the hamsters given 2 mmol of NNN, the results were: nasal cavity tumors, 5 of 21 (control) and 4 of 21 (ethanol); tracheal tumors, 9 of 21 (control) and 7 of 21 (ethanol). Thus, the carcinogenicity of NNN in the Syrian golden hamster was not affected by ethanol treatment. These results suggest that the metabolic activation of NPYR, but not that of NNN, may be enhanced by chronic ethanol consumption in the Syrian golden hamster.

Alcohol Drinking↗
PubMed1980

Assays for metabolic alpha-hydroxylation of N'-nitrosonornicotine and N-nitrosopyrrolidine and the influence of modifying factors.

High-pressure liquid chromatographic methods were developed to study microsomal alpha-hydroxylation, which is likely to be an activation mechanism for N-nitrosopyrrolidine (NPYR) and N'-nitrosonornicotine (NNN). The effects of ethanol, phenobarbital and 3-methylcholanthrene pretreatment on the alpha-hydroxylation of NPYR and NNN were determined using F-344 rats and Syrian golden hamsters. In the rat, 3-methylcholanthrene pretreatment decreased the rates of alpha-hydroxylation of NPYR and 5'-hydroxylation of NNN, but increased the rate of 2'-hydroxylation of NNN. Phenobarbital pretreatment of rats did not markedly affect rates of alpha-hydroxylation of NPYR or NNN. In the hamster, 3-methylcholanthrene pretreatment increased the rate of alpha-hydroxylation of NPYR, but did not affect the rates of alpha-hydroxylation of NNN. Phenobarbital or ethanol pretreatment of hamsters resulted in increased rates of alpha-hydroxylation of NPYR and 5'-hydroxylation of NNN. The induction of alpha-hydroxylation of NNN and NPYR by ethanol suggests that these nitrosamines may be more carcinogenic in alcohol-treated animals.

Animals↗
PubMed1979

Alpha-hydroxylation of N-nitrosopyrrolidine and N'-nitrosonornicotine by human liver microsomes.

The environmental carcinogens N-nitrosopyrrolidine (NPYR) and N'-nitrosonornicotine (NNN) were incubated with human liver microsomes to test for the presence of enzymes catalyzing alpha-hydroxylation, which is likely to be an activation mechanism for these compounds. Both nitrosamines underwent alpha-hydroxylation; rates were higher for NPYR than for NNN, as observed in rats. The results indicate that both NPYR and NNN can be metabolically activated by human liver microsomes.

Humans↗
PubMed1979

Etiological and preventive implications in alcohol carcinogenesis.

The current state of knowledge of the epidemiological association of alcohol and tobacco consumption with cancers of the head and neck in humans is reviewed. The possible involvement of alcohol-associated nutritional deficiencies in the etiology of head and neck cancer is considered. Data are presented which indicate that in vitro metabolism of the hepatocarcinogen N-nitrosopyrrolidine is increased in microsomal fractions isolated from ethanol-consuming hamsters. Relevant studies in experimental animals are discussed in the context of possible mechanisms that could account for the increased risk of cancer in heavy drinkers who smoke.

Adult↗
PubMed1979

Enhanced metabolism and mutagenesis of nitrosopyrrolidine in liver fractions isolated from chronic ethanol-consuming hamsters.

The effect of chronic ethanol consumption on the ability of isolated liver fractions to metabolize the carcinogen N-nitrosopyrrolidine (NPY) was examined. Microsomal fractions of treated animals exhibited increased rates of alpha-hydroxylation of NPY. Similar increases in the specific activities of aniline hydroxylase, reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase, and the specific content of cytochrome P-450 were also observed. In contrast, no differences in the specific activities of benzo(a)pyrene hydroxylase or glucose-6-phosphatase were observed. Liver postmitochondrial supernatants from ethanol-consuming animals were able to produce 5 times more mutants than did control preparations. It is concluded that alpha-hydroxylation of NPY is probably the mechanism by which NPY is converted to a mutagen and that this pathway can be induced by ethanol.

Alcoholism↗
PubMed1978

High pressure liquid chromatographic assay for alpha hydroxylation of N-nitrosopyrrolidine by isolated rat liver microsomes.

A high-pressure liquid chromatographic assay for alpha hydroxylation of N-nitrosopyrrolidine by isolated hepatic microsomes was developed. Mixtures consisting of N-nitrosopyrrolidine, microsomes, and an NADPH-generating system were incubated at 37 degrees. The major product of alpha hydroxylation of N-nitrosopyrrolidine, 2-hydroxytetrahydrofuran, was trapped by the addition of 2,4-dinitrophenylhydrazine reagent to form 4-hydroxybutyraldehyde-2,4-dinitrophenylhydrazone. The latter was quantified by reverse-phase high-pressure liquid chromatography. Under optimal conditions, as determined by varying protein and substrate concentrations, the alpha hydroxylation of N-nitrosopyrrolidine was linear for at least 90 min and showed characteristics typical of the microsomal mixed-function oxidase system, such as inhibition by CO and induction by pretreatment of male F-344 rats with Aroclor. N-Nitrosopyrrolidine exhibited type II spectral changes upon interaction with isolated hepatic microsomes. A close correspondence between binding affinity and alpha hydroxylation of N-nitrosopyrrolidine was observed.

Animals↗
PubMed1976

Protein synthesis in dextran sulfate-treated ascites tumor cells.

Treatment of ascites tumor cells with dextran sulfate resulted in a marked inhibition of the incorporation of [14C]valine into protein in the presence of a high Na+ medium. Amino acid incorporation was restored after i.p. injection of these cells into mice or by exposure of the cells to ascites fluid in vitro. In a medium high in K+ and low in Na+, [14C]valine incorporation into protein took place in dextran treated cells. Rotenone inhibited the reaction, which could be restored by addition of both inorganic phosphate and either glucose or glucose 6-phosphate. Quercetin, an inhibitor of the Na+-K+-ATPase, markedly depressed the incorporation of [14C]valine into protein in intact sdviyrd tumor cells in a high Na+ medium. There was little or no inhibition of protein synthesis in dextran sulfate treated cells when tested in a high K+-low Na+ medium. These experiments suggest a relationship between protein synthesis and the operation of the membranous Na+-K+-ATPase.

Adenosine Triphosphatases↗
PubMed1976

Characterization of dextran sulfate-treated ascites tumor cells and their repair by ascites fluid.

Exposure of Ehrlich ascites tumor cells to the polyanion dextran sulfate altered the permeability of the plasma membrane resulting in decreased glycolysis and respiration, enhanced permeability to Rb+ and adenosine 5'-triphosphate, and increased staining by erythrosin B. The inhibition of respiration was reversed by the addition of inorganic phosphate, whereas restoration of glycolysis required both inorganic phosphate and adenosine 5'-monophosphate. The membrane lesion was repaired by injection of dextran sulfate-treated cells into mice or by in vitro exposure to a heat-stable extract from ascites fluid. Reparied cells were no longer stained by erythrosin B and glycolyzed without added adenosine 5'-monophosphate. The time course of repaire was separable into a rapid initial repair of the membrane lesion followed by a slower recovery of the normal intracellular ionic composition. Both phases were insensitive to inhibitors of protein synthesis. The repair activity of ascites fluid was heat stable and was composed of both dialyzable and nondialyzable factors. Incubation of dextran sulfate-treated cells with ascites fluid restored Rb+ uptake and abolished the adenosine 5'-triphosphate-stimulated Ca2+ uptake.

Adenosine Monophosphate↗
PubMed1975

Characterization of the phosphoenolpyruvate inhibition of mitochondrial protein synthesis.

The interaction of phosphoenolypyruvate with isolated rat liver mitochondria has been further investigated. The uptake of P-enolpyruvate is accompanied by the stoichiometric release of intramitochondrial adenine nucleotides resulting in the inhibition of mitochondrial protein synthesis. Addition of specific inhibitors of either the adenine nucleotide carrier or the tricarboylic acid carrier blocks the P-enolpyruvate-stimulated loss of adenine nucleotides and thereby prevents the resultant inhibition of mitochondrial protein synthesis. These data suggest that there is a specific interaction between the mitochondrial adenine nucleotide translocase and the tricarboxylic acid carrier resulting in the control of intramitochondrial adenine nucleotide levels of phosphoenolpyruvate.

Adenine Nucleotides↗