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Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodiinethylamine
Department of Epidemiology and Public Health, Yale University School of Medicine New Haven, CT 06520-8034, USA
1College of Medicine, Yonsei University Seoul, South Korea
2Mc Ardle Laboratoiy for Cancer Research, University of Wisconsin Madison, WI 53706, USA
3To whom correspondence should be addressed
Capsalcin (trans-8-methyl-N-vanillyl-6-nonenamide) is a major pungent and irritating ingredient of hot chill peppers, which are frequently consumed as spices. This dietary phytochemical has been found to interact with microsomal xenobiotic metabolizing enzymes in rodents. Capsalcin and its saturated analog dihydrocapsaicin (trans 8-methyl-N-vanlllyl-6-nonanamide) have been proposed to inactivate cytochrome P-450 IIE1 by irreversibly binding to the active sites of the enzyme. Besides cytochrome P 450 IIE1, other isoforms of the P-450 superfamily were also reported to be inhibited by capsaicin. The inhibition by capsaicin of microsomal monooxygenases involved in carcinogen activation implies its chemopreventive potential. As part of a program to investigate chemoprotective properties of capsalcin we initially detennined the effect of capsalcin on vinyl carbamate (VC)- and N-nitrosodlmethyl amine (NDMA)-induced mutagenesis in Salmonella typhi murium TA 100. Capsaicin (0.42 mM) attenuated the bacterial mutagenicity of VC and NDMA by 50% and 42% respectively. Diallyl sulfide, a thloether found in garlic with selective P-450 IIE1 inhibitory activity, also lessened the mutagenicity of the above carcinogens in a concentration-dependent manner. The suppression of VC- and NDMA Induced mutagenesis by capsaicin and diallyl sulfide correlated with their inhibition of P-450 IIE1-mediated p-nltrophenol hydroxylation and NDMA N-demethylation. Pretreatment of female ICR mice with a topical dose of capsalcin lowered the average number of VC-induced skin tumors by 62% at 22 weeks after promotion. A similar degree of protection was attained with oral administration of diallyl sulfide before carcinogen treatment. The results of this study suggest that capsaicin and diallyl sulfide suppress VC- and NDMA-induced mutagenesis or tumorigenesis In part through inhibition of the cytochrome P-450 IIE1 isoform responsible for activation of these carcinogens.
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