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 on the basis of naturally occurring
isothiocyanates well known for their
lung cancer prevention properties, as a potential chemopreventive agent. In this 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 (Cyp450) 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, it 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. These results suggest that ISC-4 is a strong candidate for development as a chemopreventive agent.