Enhanced metabolism and mutagenesis of nitrosopyrrolidine in liver fractions isolated from chronic ethanol-consuming hamsters. (17/22)

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.  (+info)

Effects of dietary compounds on alpha-hydroxylation of N-nitrosopyrrolidine and N'-nitrosonornicotine in rat target tissues. (18/22)

Male F344 rats were pretreated with various dietary compounds, and the effects of pretreatment on the in vitro alpha-hydroxylation of N-nitrosopyrrolidine or N'-nitrosonornicotine were determined in assays with liver microsomes or cultured esophagus, respectively. Dietary compounds included phenols, cinnamic acids, coumarins, indoles, and isothiocyanates. Pretreatments were carried out either by administering the compound by gavage 2 hr prior to sacrifice (acute protocol) or by adding the compound to the diet for 2 weeks (chronic protocol). Acute pretreatment with benzyl isothiocyanate, allyl isothiocyanate, phenethyl isothiocyanate, phenyl isocyanate, and benzyl thiocyanate but not sodium thiocyanate inhibited formation of alpha-hydroxylation products of both nitrosamines. When the chronic pretreatment protocol was used, only phenyl isothiocyanate and sodium thiocyanate inhibited formation of alpha-hydroxylation products of both nitrosamines. Pretreatments with butylated hydroxyanisole, p-methoxyphenol, or N-acetylcysteine had little, if any, effect on the alpha-hydroxylation of N-nitrosopyrrolidine or N'-nitrosonornicotine. Chronic pretreatment with p-hydroxycinnamic acid, 4-hydroxy-3- methoxycinnamic acid, coumarin, umbelliferone, limetine , indole, indole-3-carbinol, indole-3-acetonitrile, and L-tryptophan induced activity for the alpha-hydroxylation of N-nitrosopyrrolidine. The results of this study indicate that isothiocyanates are possible candidates for further study as potential inhibitors of carcinogenesis by N-nitrosopyrrolidine and N'-nitrosonornicotine.  (+info)

High pressure liquid chromatographic assay for alpha hydroxylation of N-nitrosopyrrolidine by isolated rat liver microsomes. (19/22)

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.  (+info)

Differential effect of chronic ethanol consumption on the carcinogenicity of N-nitrosopyrrolidine and N'-nitrosonornicotine in male Syrian golden hamsters. (20/22)

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.  (+info)

A comparison of the antimutagenic potential of green, black and decaffeinated teas: contribution of flavanols to the antimutagenic effect. (21/22)

The present study was undertaken to compare the antimutagenic activity of aqueous extracts, at the concentrations used for human consumption, from green, black and decaffeinated black tea. Antimutagenic potential was evaluated against three indirect-acting dietary carcinogens, Glu-P-1, benzo(a)pyrene and nitrosopyrrolidine. All three types of tea gave rise to strong and concentration-dependent suppression of the mutagenicity of the three premutagens in the presence of an activation system. No major difference in the antimutagenic potential of the three types of tea could be discerned. Black tea, decaffeinated black tea and, to a lesser extent, green tea also antagonized the mutagenicity of the direct-acting mutagen 9-aminoacridine. All three types of tea inhibited markedly the NADPH-dependent reduction of cytochrome c and the O-dealkylations of ethoxy-, methoxy- and, to a much lesser extent, pentoxy-resorufin. When the microsomal metabolism was terminated, after the metabolic activation of the premutagens, incorporation of the aqueous tea extracts into the activation system caused a concentration-dependent suppression of mutagenic response. No significant difference in the antimutagenic activity of the three types of tea in this system was evident. Bearing in mind the much higher concentration of flavanols in green tea compared with the black teas, it may be concluded either that these compounds are unlikely to be the major tea components responsible for the antimutagenic, and possibly anticarcinogenic, properties of tea or that their fermentation products are similarly active.  (+info)

Contribution of theafulvins to the antimutagenicity of black tea: their mechanism of action. (22/22)

Theafulvins were isolated from black tea aqueous infusions and their antimutagenic activity was evaluated against a number of food carcinogens. Theafulvins gave rise to a concentration-dependent inhibition of the mutagenicity of 2-amino-3-methylimidazo-[4,5-f]quinoline, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, nitrosopyrrolidine and nitrosopiperidine, but, in contrast, the mutagenicity of aflatoxin B1 was enhanced. The mutagenicity exhibited by N'-methyl-N'-nitro-N-nitrosoguanidine and 9-aminoacridine was not influenced and weakly inhibited by theafulvins, respectively. The p-hydroxylation of aniline and the O-dealkylations of methoxy-, ethoxy- and, to a lesser extent, pentoxyresorufin were inhibited by theafulvins in a concentration-dependent manner. When microsomal metabolism was terminated after metabolic activation of the promutagens, incorporation of the theafulvins into the activation system did not modulate the mutagenic response. It is concluded that theafulvins play an important role in the antimutagenic activity of black tea by inhibiting cytochrome P450-dependent bioactivation of the carcinogens.  (+info)