Inhibitory Effects of Isothiocyanates on the Mutagenicity and Metabolism of Environmental Carcinogens
The inhibitory effects of the two naturally occuning isothiocyanates, benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) on the metabolism and mutagenicity of 4-(methylnitrosamino)-l-(3-pyridyl)-lbutanone (NNK) and benzo[a]pyrene (BaP) by F344 rat and male Syrian golden hamster liver microsomes were investigated. In addition, the alkyl chain-length effects of BITC and PEITC, together with phenyl isothiocyanate (PITC) and phenylpropyl isothiocyanate (PPITC) on the metabolism and mutagenicity of NNK, and on the metabolism of testosterone were determined. Further, the effects of all four homologues of isothiocyanates on the mutagenicity of five heterocyclic amines (HCAs) IQ, MelQx, Trp-P-2, Glu-P-2 and PhIP and on the dealkylation of ethoxyresorufin (EROD) and methoxyresorufin (MROD) were investigated. All four isothiocyanates significantly inhibited the oxidation of NNK by hamster liver microsome. The isothiocyanates enhanced the reduction of NNK by hamster liver microsome. The ability of the isothiocyanates to inhibit the a-carbon hydroxylation and pyridine N-oxidation of NNK correlated with their alkyl chain-length. The isothiocyanates exhibited little effect on the F344 rat liver mediated metabolism of NNK. Only BITC showed a significant reduction in hamster liver mediated metabolism of BaP. Both BITC and PEITC appeared to have enhanced the rat liver mediated metabolism of BaP. All four isothiocyanates inhibited the metabolism of testosterone. With the exception of Trp-P-2, a significant reduction of HCA-induced mutagenesis in TA98 was observed. A significant reduction in NNK-induced mutagenesis in TA1535 was also seen. The isothiocyanates significantly inhibited EROD and MROD activities. Since NNK, BaP and HCAs all require metabolic activation to be mutagenic, our studies indicated that isothiocyanates inhibited the activity of specific isoenzymes of cytochrome P-450.
Physiology, Isothiocyanates; Mutagenicity Tests; Carcinogenicity Tests; Carcinogens, Environmental -- metabolism
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