Metabolism of the Food Mutagen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine (PhIP) in Isolated Liver Cells from Guinea Pig, Hamster, Mouse, and Rat

Abstract

The metabolism of 2-amino-1-methyl-6-phenylimidazo [4,, the most abundant compound of the aminoimidazoazaarens (AIA) group of mutagens/carcinogens isolated from the crust of fried and broiled meat, was examined in freshly isolated hepatocytes from untreated rat, mouse, hamster, and guinea pig. Activation was evaluated by the total level of covalent binding of PhIP to macromolecules. Rat hepatocytes had the lowest rate of metabolism, both to reactive and detoxified metabolites. The products were identified as 4'-PhIP-sulfate, PhIP-glucuronide, and N(OH)-PhIPglucuronide. The ring hydroxylation rate was much greater in mouse hepatocytes, the main products being 4'-PhIP-sulfate and 4-hydroxy-PhIP. The level of covalent binding in the mouse hepatocytes exceeded those of the rat and guinea pig at high doses of PhIP. An extensive metabolism was seen in guinea pig hepatocytes, the major products being 4'-PhIP-sulfate, 4'-O-PhIP glucuronide, PhIP-glucuronide, and N(OH)-PhIP-glucuronide. In addition, several other unknown metabolites were formed. However, the amount of covalent binding in guinea pig hepatocytes was similar to that in rat hepatocytes. Covalent binding of PhIP metabolites was highest in hamster hepatocytes. Three of the main metabolites were identified as 4'-PhIP-sulfate, 4'-O-PhIP-glucuronide, and PhIP-glucuronide, but several unknown PhIP metabolites also were formed. Only minor amounts of N(OH)-PhIP-glucuronide were produced in the hamster. The present study shows that both the direct detoxification of PhIP and further conjugation of the 2-hydroxylamino-PhIP to reactive and/or detoxifie,d metabolites are important for the resulting covalent binding. -Environ Health Perspect 102(Suppl 6):109-114 (1994)

DNA Adduct Levels and Intestinal Lesions in Congenic Rapid and Slow Acetylator Syrian Hamsters Administered the Food Mutagens 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) or 2‐Amino‐3‐methylimidazo[4,5‐f]quinoline (IQ

“…A possible reason for the lack of aberrant crypt foci or tumour induction by PhIP (and possibly IQ) in hamsters may be the fact that in this species PhIP undergoes deactivation of the 4ø position at a high rate in comparison with activation by N-hydroxylation (Alexander et al 1994). However, this is also the case with rats, which show induction of aberrant crypt foci with PhIP (Takahashi et al 1991;Hasegawa et al 1993).…”

“…On the basis of our previous studies showing induction of aberrant crypt foci in the colons of congenic Syrian hamster strains after treatment with DMAB (Paulsen et al 1996;Feng et al 1996a), the fact that DMAB resembles heterocyclic amines, particularly PhIP, in structure and biotransformation (Hein 1988;Delclos & Kadlubar 1997), the known capacity of hamsters to activate heterocyclic amines (Alexander & Wallin 1991;Alexander et al 1994), and the similar levels of aberrant crypt foci induction in rats by PhIP and DMAB (Takahashi et al 1991;Hasegawa et al 1993;Steffensen et al 1995), we expected to find induction of aberrant crypt foci in hamsters administered PhIP. However, neither PhIP nor IQ induced aberrant crypt foci or tumours in either sex of two different congenic hamster strains, in experiments lasting from 10 weeks up to as long as 56 weeks.…”

“…The second step was therefore to conduct studies with heterocyclic amines in this hamster model. Previous studies (Alexander & Wallin 1991;Alexander et al 1994) have shown that hamsters have the metabolic capacity to activate heterocyclic amines to DNA reactive intermediates.…”

Food Browning and Its Prevention: An Overview

“…Metabolism. Alexander et al (1994) and Turesky et al (1994) offer the following summary of the metabolism of heterocyclic amines and the relevance of metabolic studies to human risk assessment: (a) cooked meats and fish contain more than a dozen heterocyclic amines at the low parts per billion level; (b) all amines tested are carcinogenic in rodent assays; (c) IQ is a potent carcinogen in nonhuman primates; (d) activation of the amines by human tissues is comparable to that observed in rodents; (e) the most direct evidence for genetic damage is through measurement of DNA adducts in cells and their excretion products in urine; (f) analysis of urinary metabolites can provide information on the ability of humans to metabolically activate or detoxify the procarcinogenic amines; (g) MeIQx and IQ are rapidly absorbed from the gastrointestinal tract and transformed into several detoxification products which are excreted in the urine and feces; (h) amine acetylation and N 2 -glucoronidation are important routes for the detoxification of MeIQx in rodents, nonhuman primates, and humans; and (i) human liver metabolically activates MeIQx and other amines through cytochrome-P450mediated N-oxidation and subsequent esterification reactions to produce the ultimate carcinogenic metabolites.…”