Developmental changes in hepatic activation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in rabbit.
MeIQx, a potent bacterial mutagen formed when meat is cooked, requires metabolic activation to exert its genotoxicity, a reaction catalysed primarily by CYP1A2 in adult mammals. Little is known about mammalian developmental changes in the mutagneic activation of compounds such as MeIQx. In rabbits we have shown previously that expression of CYP1A2 increases with age and is inducible by 3-methylcholanthrene (MC) from as early as 4 days pre-parturition. We have therefore investigated the effect 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 hepatic microsomal fractions from rabbits of <17 days of age. Thereafter activation 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 activation increased with age, reaching a plateau between 17 and 35 days. These rates of activation were broadly parallel to the changes in CYP1A2 specific content. These results indicate that the ability of rabbit liver to activate MeIQx is dependent on CYP1A2 activity, the expression of which is developmentally regulated. Although it has been established that human activation of MeIQx is also CYP1A2 dependent, whether a similar situation exists in infant humans has yet to be determined, although there is evidence that CYP1A2-dependent activity reaches a peak in late childhood.
Rich
K J
KJ
Clinical Pharmacology, Royal Postgraduaate Medical School, London, UK.
Zhao
K
K
Davies
D S
DS
Boobis
A R
AR
Gooderham
N J
NJ
D000367:Age Factors; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D008297:Male; D008748:Methylcholanthrene; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D011810:Quinoxalines / Q000493:pharmacokinetics*; D011817:Rabbits
D002273:Carcinogens; D011810:Quinoxalines; D008748:Methylcholanthrene; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019388:Cytochrome P-450 CYP1A2