Carcinogenesis, Vol. 20, No. 4, 615-621,
April 1999
© 1999 Oxford University Press
Comparative effects of phenylenebis(methylene)selenocyanate isomers on xenobiotic metabolizing enzymes in organs of female CD rats
American Health Foundation, 1 Dana Road, Valhalla, NY 10595, USA
The cancer chemopreventive agent 1,4-phenylenebis-(methylene)selenocyanate (p-XSC) inhibits various chemically induced tumors in laboratory animals. We examined the effects of p-XSC and its o- and m-isomers on xenobiotic metabolizing enzymes in vivo. Six-week-old female CD rats were given diets containing o-, m- or p-XSC (5 or 15 p.p.m. as Se), or equimolar amounts (30 or 90 µmol/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 microsomes, o-XSC significantly induced CYP2E1 as detected by increased N-nitrosodimethylamine N-demethylase activity and also by western blot. The activities of CYP1A1 (ethoxyresorufin-O-dealkylase) and CYP1A2 (methoxyresorufin-O-dealkylase) were not affected, but a significant decrease in the activity of CYP2B1 (pentoxyresorufin-O-dealkylase) was observed at the 15 p.p.m. Se level 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 activities were increased 1.5- to 2-fold by all three XSC isomers at the higher dose level (15 p.p.m. Se), but not by p-XTC; o-XSC again was the most effective. All three XSC isomers were found to increase the 
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isozymes of glutathione S-transferases in the liver, kidney, lung, colon and mammary gland to varying degrees. The XSC isomers also significantly increased glutathione peroxidase in the colon and mammary gland. Although o-XSC was the most powerful in stimulating the enzyme activities, especially in the liver, atomic absorption spectrometry showed that the selenium levels were highest in organs of rats given p-XSC. Thus, the level of tissue distribution of the XSC isomers and/or their metabolite(s) does not correlate with their effects on enzyme activities. The present study demonstrates that individual XSC isomers are capable of modulating specific phase I and/or phase II enzymes involved in the activation and/or detoxification of chemical carcinogens, and provides some mechanistic basis for the cancer chemopreventive efficacy of these organoselenium compounds at the stage of tumor initiation.
Abbreviations: AAS, atomic absorption spectrometry; AOM, azoxymethane; B[a]P, benzo[a]pyrene; BSC, benzyl selenocyanate; CDNB, 1-chloro-2,4-dinitrobenzene; CYP1A1, ethoxyresorufin-O-dealkylation; CYP1A2, methoxyresorufin-O-dealkylation; CYP2E1, N-nitrosodimethylamine-N-demethylase; DCNB, 1,2-dichloro-4-nitrobenzene; DMBA, 7,12-dimethylbenz[a]anthracene; GSH peroxidase, glutathione peroxidase; GST, glutathione S-transferase; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; o-XSC, m-XSC and p-XSC, 1,2- 1,3- and 1,4-phenylenebis(methylene)selenocyanate; p-NP, p-nitrophenol; p-XTC, 1,4-phenylenebis(methylene)thiocyanate; UDPGT, UDP-glucuronosyltransferase.
1 To whom correspondence should be addressed
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