CHEMOPREVENTIVE POTENTIAL OF THIOL CONJUGATES OF ISOTHIOCYANATES FOR LUNG-CANCER AND A URINARY BIOMARKER OF DIETARY ISOTHIOCYANATES

Natural and synthetic isothiocyanates (ITCs) are versatile chemopreven tive agents in many animal systems. We have shown that phenethyl ITC ( PEITC) and 6-phenylhexyl ITC (PHITC) are potent inhibitors against lun g tumorigenesis induced by tobacco nitrosamine 3-(methylnitrosamino)-1 -(3-pyridyl)-1-butanone (NNK) in both mouse and rat. The mechanism by which these ITCs inhibited lung tumorigenesis is attributed to their a bility to decrease cytochrome P450 (P450) enzyme activities involved i n the activation of NNK. Recently, we have found that thiol conjugates of ITCs inhibit P450 enzymes and are effective inhibitors of lung tum origenesis. This is significant because conjugation With cellular thio ls is the major route of ITC metabolism via the mercapturic acid pathw ay in rodents and humans. The thiol conjugates are less pungent and po tentially less toxic, and they are more soluble and chemically less re active than ITCs. These properties raise the prospect of substituting thiol conjugates for ITCs as chemopreventive agents. Furthermore, alth ough ample rodent studies have established that ITCs inhibit tumorigen esis, the protective role of dietary ITCs against human cancers has no t yet been established. As a prerequisite for such human studies, we h ave developed an HPLC-based assay, based on the condensation reaction of ITCs or conjugates with 1,2-benzenedithiol, for measuring a cycloco ndensation product in human urine as an uptake biomarker of total ITCs . This assay was validated using urine samples from subjects who had i ngested a known amount of watercress or mustard in a controlled diet. The assay is convenient and rapid, showing promise for analyzing urine samples obtained from population-based studies. Results from two such studies are presented to illustrate the potential application of this biomarker in epidemiologic studies. (C) 1998 Wiley-Liss, Inc.