INHIBITION OF MUTAGENESIS OF 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE (IQ) BY COUMARINS AND FURANOCOUMARINS, CHROMANONES AND FURANOCHROMANONES

A total of 51 natural and synthetic simple coumarins, furanocoumarins, chromanones, furanochromanones and some structurally related compound s were tested for their antimutagenic potencies with respect to IQ in Salmonella typhimurium TA 98. Antimutagenic potencies were quantified by the inhibitory dose for 50% reduction of mutagenic activity (ID50) and by the remaining mutagenic activity at the highest dose tested. An timutagenic activities of the parent compounds were weak (ID50: 500-75 0 nmol/plate) but increased in the coumarin series with introduction o f hydroxy, methoxy and (or) methyl groups at carbons 4, 5, 6 and 7 (ID 50: 70-400 nmol/plate). However, the antimutagenicity of compounds wit h hydroxy or methoxy substituents at C-5, C-6 and C-7 all together was low. Moreover, a hydroxy or methoxy function at C-8 greatly reduced a ntimutagenic potency. This was in part also true for substituents at C -3. Coumarin glycosides and glucuronides of antimutagenic aglycones we re, however, inactive. Introduction of a carboxyl function rendered th e respective coumarin inactive. Surprisingly, some synthetic coumarins with a bromo or iodo substituent at C-8 or a benzyloxy function at C- 5 were found to be very potent antimutagens (ID50: 9.3-14.5 nmol/plate ), whereas analogues possessing a bromo or formyl function at C-5 were less effective (ID50: 176 and 395 nmol/plate). Furanocoumarins and fu ranochromanones were very potent antimutagens (ID50: 5.1-26.5 nmol/pla te). In enzyme kinetic experiments with Salmonella the inhibition mech anisms of xanthotoxin and visnagin were concentration dependent, being non-competitive at low concentrations. Reduction of the activity of 7 -ethoxy- and 7-methoxyresorufin-O-dealkylases with IC50 values of 1.2- 11.7 mu M indicated strong inhibition of cytochrome P-450 1A1 and 1A2 dependent monooxygenases by some of the furanocoumarines and -chromano nes. The mutagenic activity of N-hydroxy-IQ in Salmonella, however, wa s not reduced by any of these compounds. In various experiments design ed for modulation of the mutagenic response inhibition of activation o f IQ to N-OH-IQ was found to be the only relevant mechanism of antimut agenesis of psoralen, angelicin and khellin.