Chemoprevention of lung tumorigenesis induced by a mixture of benzo(a)pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by the organoseleniumcompound 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 mu mol/mouse) and NN K (3 mu mol/mouse) in cottonseed oil (0.1 mi) once a week for eight consecu tive weeks. Mice were fed either AIN-76A control diet or control diet conta ining p-XSC (10 ppm selenium), either during or after carcinogen administra tion. Dietary p-XSC significantly reduced lung tumor multiplicity, regardle ss of whether it was given during or after carcinogen administration. p-XSC was also an effective inhibitor of tumor development in the forestomach. T o provide some biochemical insights into the protective role of p-XSC, its effect on selected phase I and II enzyme activities involved in the metabol ism of NNK and B(a)P was also examined in vivo in this animal model. Dietar y p-XSC significantly inhibited the activities of the phase I enzymes, meth oxyresorufin O-dealkylase (MROD) and N-nitrosodimethylamine N-demethylase ( NDMAD), in mouse liver, but it had no effect on ethoxyresorufin O-dealkylas e (EROD), pentoxyresorufin O-dealkylase (PROD), and erythromycin N-demethyl ase (ERYTD). Total glutathione S-transferase (GST) enzyme activity, as well as GST-pi and GST-mu enzyme activities, were significantly induced by diet ary 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-X SC had no effect on selenium-dependent glutathione peroxidase (GPX(Sc)), GS T-alpha, and UDP-glucuronosyl transferase (UDPGT) enzyme activities in eith er the lung or the liver. These studies suggest that the chemopreventive ef ficacy of p-XSC, when fed during carcinogen administration, may be, in part . due to the inhibition of certain phase I enzymes involved in the metaboli c activation of these carcinogens, and the induction of specific phase II e nzymes involved in their detoxification. The mechanisms that account for th e effect of p-XSC when fed after carcinogen administration remain to be det ermined. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.