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. 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 micromol/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 alpha, mu and pi 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.
Sohn
O S
OS
American Health Foundation, Valhalla, NY 10595, USA.
Fiala
E S
ES
Upadhyaya
P
P
Chae
Y H
YH
El-Bayoumy
K
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D007536:Isomerism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D016566:Organoselenium Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012643:Selenium / Q000032:analysis; D014018:Tissue Distribution
D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D016566:Organoselenium Compounds; C074153:1,4-phenylenebis(methylene)selenocyanate; D003577:Cytochrome P-450 Enzyme System; D005979:Glutathione Peroxidase; D014453:Glucuronosyltransferase; D012643:Selenium