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At least 1,297 records · Page 72Linked to original sources
PubMed1993

Effects of capsaicin on liver microsomal metabolism of the tobacco-specific nitrosamine NNK.

Chemically-induced mutagenesis and carcinogenesis is modulated by various plant products, some of which are present in the human diet. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent carcinogen in tobacco and tobacco smoke, is activated by microsomal enzymes. In this study, we investigated the effects of capsaicin on the in vitro metabolism of NNK. Capsaicin is the principal component of Capsicum fruits used widely by humans as a food additive. Liver microsomes from saline-injected, phenobarbital-induced and beta-naphthoflavone-induced hamsters were used. Microsomes from phenobarbital and beta-naphthoflavone-induced animals expressed decreased NNK reduction and enhanced pyridine-N-oxidation, but did not significantly alter alpha-carbon hydroxylation of NNK. Capsaicin (0.5 mM) inhibited the formation of all metabolites of NNK by all microsomal fractions and inhibited alpha-hydroxylation by phenobarbital-induced microsomes more than by either of the other two treatments. Our results suggest that capsaicin, as a naturally occurring dietary constituent, possesses antimutagenic and anticarcinogenic properties through the inhibition of xenobiotic metabolizing enzymes.

Animals↗
PubMed1996

G --> A mutation of ras genes and infrequent p53 gene mutation in rat transplantable thyroid carcinoma lines from tumors induced in vivo by N-bis(2-hydroxypropyl)nitrosamine.

In a comparative study, we have investigated mutational activation of three kinds of ras genes and the p53 gene (exons 5-8) in 19 rat transplantable thyroid carcinoma lines derived from in vivo tumors induced by DHPN. Mutations were identified using single-strand conformation polymorphism and DNA sequencing analysis, and activated ras oncogenes were detected in 6 lines (31%). These all had mutations in Ki-ras codons at 12 or 63, and one of them also possessed a Ha-ras mutation at codon 12 as a double mutation. Three mutations of Ki-ras at codon 12 involved the second nucleotide and two the first position, the other being found at the first nucleotide in codon 63. Base alterations of p53 gene were found in two lines. One had an insertion of 1 base (thymine) between codon 206 and codon 207. Historically, it was diagnosed as a poorly differentiated papillary carcinoma (scirrhous pattern). In the another case, there was no amino acid change although one base substitution occurred at codon 283 (GAG --> GAA) of exon 8. These results indicate that, in the ras family, DHPN induces Ki-ras gene activation preferentially and that p53 mutation may be infrequent in thyroid carcinogenesis in rats, our data thus corresponding well with the previous reports that an inactivated p53 gene only plays a major role in human undifferentiated thyroid carcinomas.

Adenine↗
PubMed2003

Phenethyl isothiocyanate inhibits nitrosamine carcinogenesis in a model for study of oral cancer chemoprevention.

The anticarcinogenic effect of phenethyl isothiocyanate (PEITC) was examined in hamster buccal pouch mucosa exposed to N-nitrosomethylbenzylamine (NMBA). Unscheduled DNA synthesis (UDS) and induction of intraepithelial gamma-glutamyl transpeptidase (gamma-GT) histochemical foci were assessed as potential predictors of anticarcinogenicity. UDS mediated by in vitro exposure to NMBA (at 10 and 50 mM) was examined in mucosal samples derived following topical exposure of pouch mucosa to PEITC at concentrations of 0.5, 5, or 50 mM. In vivo PEITC pretreatment reduced NMBA-induced UDS in a dose dependent manner. PEITC treatment reduced induction of gamma-GT foci, detected in epithelial wholemounts derived over a period of 8-13 weeks of NMBA application, by an average of 96%. PEITC also reduced tumor formation by 94%. gamma-GT, in particular, may be a useful indicator for identification of effective oral cancer chemopreventive agents and combinations of agents.

Animals↗
PubMed2003

Cytochrome b5 reductase and cytochrome b5 support the CYP2E1-mediated activation of nitrosamines in a recombinant Ames test.

With CYP2E1 in vitro both the first and the second electron of the catalytic cycle can come from cytochrome b(5) via either NADPH-cytochrome P450 reductase or NADH-cytochrome b(5) reductase, and the presence of cytochrome b(5) stimulates CYP2E1 turnover both in vitro and in vivo. To determine whether electron input via the NADH-dependent pathway was similarly functional in whole cells and necessary for the stimulation by cytochrome b(5), we constructed five plasmids designed to express human CYP2E1 in various combinations with cytochrome b(5) reductase, cytochrome b(5), and cytochrome P450 reductase. CYP2E1 activity in Salmonella typhimurium cells transformed with each plasmid was assessed by mutagenic reversion frequency in the presence of dimethylnitrosamine. A fivefold increase in reversion frequency when cytochrome b(5) was coexpressed with P450 reductase was abolished by disruption of heme-binding in cytochrome b(5) by site-directed mutagenesis (His68Ala), suggesting that electron transfer to cytochrome b(5) was necessary for the stimulation. Addition of cytochrome b(5) reductase to the cytochrome b(5)/P450 reductase coexpression plasmid did not further increase the stimulation by cytochrome b(5), but b(5) reductase could support CYP2E1 activity in the absence of P450 reductase at a level equivalent to that obtained with just CYP2E1 and P450 reductase. Neither cytochrome b(5) reductase nor cytochrome b(5) alone could support CYP2E1 activity. These results demonstrate that the cytochrome b(5) reductase/cytochrome b(5) pathway can support CYP2E1 activity in bacterial cells.

Cytochrome P-450 CYP2E1↗
PubMed1998

Preferential effects of nicotine and 4-(N-methyl-N-nitrosamine)-1-(3-pyridyl)-1-butanone on mitochondrial glutathione S-transferase A4-4 induction and increased oxidative stress in the rat brain.

We have investigated the in vivo effects of the tobacco-specific toxins nicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on antioxidant defense systems in the mitochondrial, microsomal, and cytosolic compartments of rat brain, lung, and liver. Nicotine induced maximum oxidative stress in brain mitochondria, as seen from a 1.9-fold (P < 0.001) increase in thiobarbituric acid-reactive substance (TBARS) and a 2-fold (P < 0.001) increase in glutathione S-transferase (GST) A4-4 (also referred to as rGST 8-8) activities. These changes were accompanied by a 25-40% increase in reactive oxygen species and a 20-30% decrease in alcohol dehydrogenase activities. The 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone-induced oxidative damage was apparent in the microsomal fraction of brain, lung, and liver, and it also increased 4-hydroxynonenal specific GST A4-4 activity in the brain and lung mitochondrial matrix fraction. The levels of microsomal thiobarbituric acid reactive substance, cytochrome P4502E1 activity, and reactive oxygen species were also increased significantly (P < 0.001) in all tissues. Both of these toxins induced the level of GST A4-4 mRNA in the brain, while they caused a marked reduction in the liver GST A4-4 mRNA pool. Additionally, the brain mitochondrial matrix showed a markedly higher level of 4-hydroxynonenal specific GST activity and mGST A4-4 antibody-reactive protein than did the cytosolic fraction. In conclusion, the present study provides evidence for the occurrence of GST A4-4 enzyme activity in mammalian mitochondria, in addition to demonstrating that both mitochondria and microsomes are intracellular targets for nicotine- and NNK-induced organ toxicity.

Animals↗