Phenylbutyl Isoselenocyanate Modulates Phase I and II Enzymes and Inhibits 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induced DNA Adducts in Mice

摘要

Lung cancer remains one of the most preventable forms of cancer with about 90% of cases attributed to cigarette smoking. Over the years, the development of chemopreventive agents that could inhibit, delay, or reverse the lung carcinogenesis process has been an active field of research, however, without much attainment. Through extensive structure-activity relationship studies, we recently identified a novel agent phenylbutyl isoselenocyanate (ISC-4), designed based on naturally occurring isothiocyanates well known for their lung cancer prevention properties, as a potential chemopreventive agent. In the present study, we used A/J mice to evaluate the lung cancer chemopreventive potential of ISC-4. A single intragastric dose of 1.25 µmol ISC-4 resulted in a time-dependent increase of selenium levels in serum, liver, and lung, suggesting that ISC-4 is orally bioavailable, a key requirement for a chemopreventive agent. This dose also resulted in a time dependent inhibition of microsomal cytochrome P450 (Cyp) activity and delayed increases in Phase II UDP-glucuronyl transferase (Ugt) and glutathione-S-transferase (Gst) activity. ISC-4 was able to induce mRNA expression of Cyp, Ugt, and Gst enzyme isoforms in liver, but in lung inhibited Cyp isoforms while inducing Ugt and Gst isoforms. In addition, ISC-4 effectively inhibited methyl-DNA adduct formation in mice fed diet supplemented with ISC-4 for two weeks and then treated with the tobacco procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent.