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New potential chemopreventive agents for lung carcinogenesis of tobacco-specific nitrosamine
F L Chung1, M A Morse, K I Eklind
1American Health Foundation, Valhalla, New York 10595.
Abstract:
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)-1-(3-pyridyl)-1-butanone. Several aromatic isothiocyanates have been identified as effective inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. Phenethyl isothiocyanate, a natural constituent of cruciferous vegetables, protects F344 rats and A/J mice from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. The alkyl chain length in the aromatic isothiocyanates is an important structural feature for the inhibitory potency. The inhibitory efficacy increases as the alkyl chain elongates up to 6 carbon atoms. Thus, 6-phenylhexyl isothiocyanate is approximately 50 to 100 times more potent than phenethyl isothiocyanate. The remarkable efficiency of 6-phenylhexyl isothiocyanate suggests 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 N-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 gluconasturtiin, the glucosinolate precursor of phenethyl isothiocyanate. Considering 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.
Insights
Chemopreventive agents like 6-phenylhexyl isothiocyanate show promise against lung cancer caused by smoking. A urinary marker can now track dietary intake of related compounds like phenethyl isothiocyanate.
Area of Science:
- Oncology
- Chemoprevention
- Biochemistry
Background:
- Cigarette smoking is a primary cause of lung cancer globally.
- Tobacco-specific nitrosamines, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, are potent carcinogens.
- Developing effective chemopreventive strategies is crucial to combat rising lung cancer rates.
Purpose of the Study:
- To identify and evaluate novel chemopreventive agents against lung carcinogenicity induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
- To investigate the structure-activity relationship of aromatic isothiocyanates as lung cancer inhibitors.
- To develop a method for monitoring human exposure to dietary chemopreventive compounds.
Main Methods:
- Screening of aromatic isothiocyanates for inhibitory activity against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in rodent models.
- Structure-activity relationship studies focusing on the alkyl chain length of isothiocyanates.
- Pharmacokinetic studies on phenethyl isothiocyanate in mice, including tissue distribution and metabolite identification.
- Development of a urinary marker to quantify phenethyl isothiocyanate uptake in humans.
Main Results:
- Phenethyl isothiocyanate, found in cruciferous vegetables, demonstrated protective effects against lung tumorigenesis in rats and mice.
- Inhibitory potency of aromatic isothiocyanates increased with alkyl chain length, with 6-phenylhexyl isothiocyanate being 50-100 times more potent than phenethyl isothiocyanate.
- Major urinary metabolites of phenethyl isothiocyanate were identified as mercaptopyruvic acid and N-acetylcysteine conjugates.
- A urinary marker was successfully developed to measure phenethyl isothiocyanate uptake in humans.
Conclusions:
- 6-Phenylhexyl isothiocyanate exhibits significant potency and warrants further investigation as a chemopreventive agent for lung cancer.
- Dietary intake of phenethyl isothiocyanate from sources like watercress can be monitored using the developed urinary marker.
- This marker holds potential for assessing the role of dietary chemopreventive compounds in lung cancer risk reduction.