New Potential Chemopreventive Agents for Lung Carcinogenesis of Tobacco- specific Nitrosamine1

Cigarette smoking is the major cause of lung cancer in humans. The continuous increase in the prevalence of cigarette smoking worldwide demands a practical means to circumvent this serious health problem. Our research has focused on the development of new chemopreventive agents against lung carcinogenicity of the tobacco-specific nitrosamine 4(methylnitrosamino)-l-(3-pyridyl)-l-butanone. Several aromatic isothiocyanates have been identified as effective inhibitors of 4-( met h>Inii rosamino)-l-(3-pyridyl)-l-butanone-induced lung tumorigenesis. Phenethyl isothiocyanate, a natural constituent of cruciferous vegetables, protects F344 rats and A/J mice from 4-{methylnitrosamino)-l-(3-pyridyl)-lbutanone-induced lung tumorigenesis. The alkyl chain length in the aromatic isothiocyanates is an important structural feature for the inhib itory potency. The inhibitory efficacy increases as the alkyl chain elon gates up to 6 carbon atoms. Thus, 6-phenylhexyl isothiocyanate is approximately 50 to 100 times more potent than phenethyl isothio cyanate. The remarkable efficiency of 6-phenylhexyl isothiocyanate sug gests its potential as a chemopreventive agent in intervention trials. The tissue distribution and excretion of phenethyl isothiocyanate were studied in mice. Two major urinary metabolites were identified as the mercaptopyruvic acid and the A'-acetylcysteine conjugates. A urinary marker was developed to quantitate the uptake of phenethyl isothiocyanate in humans after consumption of watercress, a cruciferous vegetable rich in gluconasturtun, the glucosinolate precursor of phenethyl isothiocyanate. Con sidering the anticarcinogenic activity of phenethyl isothiocyanate, this marker may eventually be useful in assessing the role of dietary phenethyl isothiocyanate uptake in lung cancer risk.