DEVELOPMENTAL-CHANGES IN HEPATIC ACTIVATION OF 2-AMINO-3,8-DIMETHYLIMIDAZO[4,5-F] QUINOXALINE IN RABBIT

MeIQx, potent bacterial mutagen formed when meat is cooked, requires m etabolic activation to exert its genotoxicity, a reaction catalysed pr imarily by CYP1A2 in adult mammals, Little is known about mammalian de velopmental changes in the mutagenic activation of compounds such as M eIQx, In rabbits we have shown previously that expression of CYP1A2 in creases with age and is inducible by 3-methylcholanthrene (MC) from as early as 4 days pre-parturition. We have therefore investigated the e ffect of age on rabbit liver activation of MeIQx (assessed in an Ames test using Salmonella typhimurium TA98) before and after treatment of the animals with MC, MeIQx activation could not be detected using hepa tic microsomal fractions from rabbits of <17 days of age. Thereafter a ctivation increased with age to peak in weanling animals, Following MC treatment MeIQx activation was increased, being detectable in samples from rabbits as young as 9-11 days, The inducibility of MeIQx activat ion increased with age, reaching a plateau between 17 and 35 days, The se rates of activation were broadly parallel to the changes in CYP1A2 specific content. These results indicate that the ability of rabbit li ver to activate MeIQx is dependent on CYP1A2 activity, the expression of which is developmentally regulated, Although it has been establishe d that human activation of MeIQx is also CYP1A2 dependent, whether a s imilar situation exists in infant humans has yet to be determined, alt hough there is evidence that CYP1A2-dependent activity reaches a peak in late childhood.