Chemoprevention of lung tumorigenesis induced by a mixture of benzo(a)pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.
We evaluated the chemopreventive efficacy of the organoselenium compound 1,4-phenylenebis(methylene)selenocyanate (p-XSC) against the development of tumors of the lung and forestomach induced by a mixture of benzo(a)pyrene (B(a)P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), two of the major lung carcinogens present in tobacco smoke. A/J mice (20 mice/group) were given intragastric doses of a mixture of B(a)P (3 micromol/mouse) and NNK (3 micromol/mouse) in cottonseed oil (0.1 ml) once a week for eight consecutive weeks. Mice were fed either AIN-76A control diet or control diet containing p-XSC (10 ppm selenium), either during or after carcinogen administration. Dietary p-XSC significantly reduced lung tumor multiplicity, regardless of whether it was given during or after carcinogen administration. p-XSC was also an effective inhibitor of tumor development in the forestomach. To provide some biochemical insights into the protective role of p-XSC, its effect on selected phase I and II enzyme activities involved in the metabolism of NNK and B(a)P was also examined in vivo in this animal model. Dietary p-XSC significantly inhibited the activities of the phase I enzymes, methoxyresorufin O-dealkylase (MROD) and N-nitrosodimethylamine N-demethylase (NDMAD), in mouse liver, but it had no effect on ethoxyresorufin O-dealkylase (EROD), pentoxyresorufin O-dealkylase (PROD), and erythromycin N-demethylase (ERYTD). Total glutathione S-transferase (GST) enzyme activity, as well as GST-pi and GST-mu enzyme activities, were significantly induced by dietary p-XSC in both the lung and liver. Glutathione peroxidase (GPX) activity was also induced by p-XSC in mouse lung, but not in the liver. Dietary p-XSC had no effect on selenium-dependent glutathione peroxidase (GPX(Se)), GST-alpha, and UDP-glucuronosyl transferase (UDPGT) enzyme activities in either the lung or the liver. These studies suggest that the chemopreventive efficacy of p-XSC, when fed during carcinogen administration, may be, in part, due to the inhibition of certain phase I enzymes involved in the metabolic activation of these carcinogens, and the induction of specific phase II enzymes involved in their detoxification. The mechanisms that account for the effect of p-XSC when fed after carcinogen administration remain to be determined.
Prokopczyk
B
B
American Health Foundation, Valhalla, NY 10595, USA.
Rosa
J G
JG
Desai
D
D
Amin
S
S
Sohn
O S
OS
Fiala
E S
ES
El-Bayoumy
K
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D004334:Drug Administration Schedule; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008805:Mice, Inbred A; D009602:Nitrosamines / Q000493:pharmacokinetics / Q000633:toxicity*; D016566:Organoselenium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000517:prevention & control
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D007527:Isoenzymes; D009602:Nitrosamines; D016566:Organoselenium Compounds; D001564:Benzo(a)pyrene; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C074153:1,4-phenylenebis(methylene)selenocyanate; D005982:Glutathione Transferase