STRUCTURE-ACTIVITY-RELATIONSHIPS OF ARYLALKYL ISOTHIOCYANATES FOR THEINHIBITION OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE METABOLISM AND THE MODULATION OF XENOBIOTIC-METABOLIZING ENZYMES IN RATS AND MICE

Many arylalkyl isothiocyanates are potent inhibitors of 4-(methylnitro samino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in r ats and mice. In the mouse, 4-phenylbutyl isothiocyanate (PBITC) and 6 -phenylhexyl isothiocyanate (PHITC) exhibited greater inhibition than benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC). The present study was conducted to investigate the structure-activity rel ationships of these four arylalkyl isothiocyanates for their inhibitio n of NNK oxidation and effects on xenobiotic-metabolizing enzymes in r ats and mice. A single dose (0.25 or 1.00 mmol/kg) of each isothiocyan ate was given to F344 rats 6 or 24 h before death. The rates of NNK ox idation were decreased in microsomes from the liver, lung and nasal mu cosa of rats. Generally, PEITC was more potent than BITC but less pote nt than PBITC and PHITC. The rates in rat liver microsomes were decrea sed at 6 h but recovered or increased at 24 h; the rates in rat lung m icrosomes were markedly decreased at both 6 and 24 h; and the rates in rat nasal mucosa microsomes were also significantly decreased. The sa me treatment decreased the rat liver N-nitrosodimethylamine demethylas e activity dramatically and ethoxyresorufin O-dealkylase and erythromy cin N-demethylase activities moderately. However, the rat liver micros omal pentoxyresorufin O-dealkylase activity was decreased at 6 h but i ncreased at 24 h, with PEITC showing the most marked induction. The ra t liver NAD(P)H:quinone oxidoreductase activity was increased 1.4- to 3.3-fold, with PEITC being most effective; and the glutathione S-trans ferase activity was increased slightly. Similarly, at a single dose of 0.25 mmol/kg (5 mumol/mouse) 24 h before death, PEITC, PBITC, PHITC b ut not BITC, decreased NNK oxidation in mouse lung microsomes by 40-85 %, with PBITC and PHITC showing greater inhibition. Furthermore, all f our isothiocyanates extensively inhibited NNK oxidation in rat lung an d nasal mucosa microsomes as well as mouse lung microsomes in vitro, w ith PEITC (IC50 of 120-300 nM) being more potent than BITC (IC50 of 50 0-1400 nM) but less potent than PBITC and PHITC (IC50 of 15-180 nM). P HITC was a very potent competitive inhibitor of NNK oxidation in mouse lung microsomes with apparent K(i) values of 11-16 nM. These results indicate that PBITC and PHITC are more potent inhibitors of NNK bioact ivation in rats and mice than PEITC. In addition, these arylalkyl isot hiocyanates could be effective in protecting against the actions of a broad spectrum of carcinogenic or toxic compounds.