CHEMOPROTECTIVE EFFECTS OF CAPSAICIN AND DIALLYL SULFIDE AGAINST MUTAGENESIS OR TUMORIGENESIS BY VINYL CARBAMATE AND N-NITROSODIMETHYLAMINE

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a major pungent and irritating ingredient of hot chilli peppers, which are frequently consumed as spices, This dietary phytochemical has been found to inter act with microsomal xenobiotic metabolizing enzymes in rodents. Capsai cin and its saturated analog dihydrocapsaicin (trans-8-methyl-N-vanill yl-6-nonanamide) have been proposed to inactivate cytochrome P-450 IIE 1 by irreversibly binding to the active sites of the enzyme, Besides c ytochrome P-450 IIE1, other isoforms of the P-450 superfamily were als o reported to be inhibited by capsaicin. The inhibition by capsaicin o f microsomal monooxygenases involved in carcinogen activation implies its chemopreventive potential. As part of a program to investigate che moprotective properties of capsaicin we initially determined the effec t of capsaicin on vinyl carbamate (VC)- and N-nitrosodimethylamine (ND MA)-induced mutagenesis in Salmonella typhimurium TA100. Capsaicin (0. 42 mM) attenuated the bacterial mutagenicity of VC and NDMA by 50% and 42% respectively. Diallyl sulfide, a thioether found in garlic with s elective P-450 IIE1 inhibitory activity, also lessened the mutagenicit y of the above carcinogens in a concentration-dependent manner. The su ppression of VC- and NDMA-induced mutagenesis by capsaicin and diallyl sulfide correlated with their inhibition of P-450 IIE1-mediated p-nit rophenol hydroxylation and NDMA N-demethylation. Pretreatment of femal e ICR mice with a topical dose of capsaicin lowered the average number of VC-induced skin tumors by 62% at 22 weeks after promotion. A simil ar degree of protection was attained with oral administration of diall yl sulfide before carcinogen treatment. The results of this study sugg est that capsaicin and diallyl sulfide suppress VC- and NDMA-induced m utagenesis or tumorigenesis in part through inhibition of the cytochro me P-450 IIE1 isoform responsible for activation of these carcinogens.