title: Species differences in the biotransformation of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by hepatic microsomes and cytosols from humans, rats, and mice.
abstract: A comparative study on the metabolic activation and detoxification of the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), by human, rat, and mouse hepatic subcellular fractions was conducted to elucidate the mechanism of the interspecies and organ-specific differences in genotoxicity and carcinogenesis. Incubation of PhIP with human, rat, and mouse hepatic microsomes each generated two metabolites, which were identified as N-hydroxy-PhIP and 4'-hydroxy-PhIP. However, the rates of formation of these metabolites differed significantly between species. Human hepatic microsomes had the highest capacity to convert PhIP to the genotoxic metabolite, N-hydroxy-PhIP, with a mean +/- SD value (9.69 +/- 5.15 nmol/mg protein/30 min, N = 3) that was 1.8-fold and 1.4-fold higher than that of rats (5.25 +/- 1.63, N = 3) and mice (6.89 +/- 0.55, N = 3) p < 0.05), respectively. Rodent microsomes were also able to convert PhIP to its nongenotoxic 4'-hydroxy derivative; however, this detoxification pathway was negligible in human hepatic microsomes. The ratio of N-hydroxylation to 4'-hydroxylation was 97:1, 3.3:1, and 1.7:1 for humans, rats, and mice, respectively. The capacities for the further metabolic activation of N-hydroxy-PhIP by cytosolic O-acetyltransferase, sulfotransferase, L-prolyl-tRNA synthetase, and an ATP-dependent kinase(s) were examined using PhIP-DNA binding as a measure of bioactivation. Acetyl coenzyme A-dependent DNA binding of N-hydroxy-PhIP was detected with both human and rodent hepatic cytosols, and showed a significant interspecies difference.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: National Center for Toxicological Research, Jefferson, AR 72079-9502, USA.
authors.forename: D X
authors.initials: DX
authors.lastname: Lin
authors.forename: N P
authors.initials: NP
authors.lastname: Lang
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
mesh_terms: D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
chemical_list: D002273:Carcinogens; D007093:Imidazoles; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D005982:Glutathione Transferase