Comparative effects of phenylenebis(methylene)selenocyanate isomers on xenobiotic metabolizing enzymes in organs of female CD rats

The cancer chemopreventive agent 1,4-phenylenebis-(methylene)selenocyanate (p-XSC) inhibits various chemically induced tumors in laboratory animals, W e examined the effects of p-XSC and its o- and m-isomers on xenobiotic meta bolizing enzymes in vivo. Six-week-old female CD rats were given diets cont aining o-, m- or p-XSC (5 or 15 p.p.m. as Se), or equimolar amounts (30 or 90 mu mol/kg) of 1,4-phenylenebis(methylene)thiocyanate (p-XTC, the sulfur analog of p-XSC) for 1 week. At termination, substrate-specific assays for enzymes of xenobiotic metabolism in various organs were performed. Overall, o-XSC was a more potent enzyme inducer than m- or p-XSC, In hepatic micros omes, o-XSC significantly induced CYP2E1 as detected by increased N-nitroso dimethylamine N-demethylase activity and also by western blot. The activiti es of CYP1A1 (ethoxyresorufin-O-dealkylase) and CYP1A2 (methoxyresorufin-O- dealkylase) were not affected, but a significant decrease in the activity o f CYP2B1 (pentoxyresorufin-O-dealkylase) was observed at the 15 p.p.m. Se l evel of o-XSC, With the m- and p-XSC isomers or with p-XTC, no significant effect on phase I enzymes was noted. Hepatic UDP-glucuronosyltransferase ac tivities were increased 1,5-to 2-fold by all three XSC isomers at the highe r dose level (15 p.p.m. Se), but not by p-XTC; o-XSC again was the most eff ective. All three XSC isomers were found to increase the alpha, mu and pi i sozymes of glutathione S-transferases in the liver, kidney, lung, colon and mammary gland to varying degrees. The XSC isomers also significantly incre ased glutathione peroxidase in the colon and mammary gland, Although o-XSC was the most powerful in stimulating the enzyme activities, especially in t he liver, atomic absorption spectrometry showed that the selenium levels we re highest in organs of rats given p-XSC, Thus, the level of tissue distrib ution of the XSC isomers and/or their metabolite(s) does not correlate with their effects on enzyme activities. The present study demonstrates that in dividual XSC isomers are capable of modulating specific phase I and/or phas e II enzymes involved in the activation and/or detoxification of chemical c arcinogens, and provides some mechanistic basis for the cancer chemoprevent ive efficacy of these organoselenium compounds at the stage of tumor initia tion.