The effect of dose and enzyme inducers on the metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats

Abstract

Male Fischer 344 rats were given a single dose of 0.03-30 mg/kg of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ([14C]PhIP), the radioactivity in urine and feces was determined over 48 h, and the major metabolites were identified and quantified. Dose had little effect on the profile of metabolites in the urine but did influence the profile in the feces. PhIP was more efficiently metabolized at higher doses. In addition, rats were pretreated with Aroclor 1254 (PCB), 3-methylcholanthrene (MC), phenobarbital (PB), PhIP and corn oil prior to a single dose of [14C]PhIP, and compared with a control group receiving [14C]PhIP only. The major metabolites in the urine and feces were quantitated for each group, as well as PhIP binding to serum proteins, hemoglobin and selected tissues. Pretreatment with MC and PCB resulted in an increase in the amount of 4'-hydroxylation of PhIP and a decrease in the amount of N-hydroxylated metabolites in the urine. Pretreatment with PB resulted in an increase in the amount of N-hydroxylated metabolites, but a decrease in 4'-hydroxylation. Pretreatment with either MC or PCB resulted in an increase in PhIP binding to the liver and kidney, while reducing the binding in other tissues. Animals pretreated with PhIP showed few significant differences from the untreated group, while pretreatment with PB in general resulted in a decrease of PhIP binding in tissues.

Heterocyclic amines: evaluation of their role in diet associated human cancer

“…Studies with rodents have demonstrated that both MeIQx and PhIP are C-and N-oxidised, amine [17], which is consistent with the HAs being extensively absorbed and bioavailable. We have studied, glucuronidated, acetylated and form sulphamates [16, [21][22][23][24][25][26]. The pathway by which the HAs are activated on over 100 separate occasions, normal human volunteers fed standard fried beef meals containing variable amounts to genotoxins involves N-oxidation of the exocyclic amine function to the N-hydroxylamine, whereas ring of HAs (250-7500 ng of HA, determined by gas chromatography-mass spectrometry, GC-MS) and have shown C-hydroxylation is a detoxication reaction.…”

“…All of the heterocyclic amines tested thus far, including of mutants tumours in a variety of tissues (Table 4 ) In these bioassays, carcinogen dosage is considerably −exon 5 1 higher than the calculated daily human exposure; but −exon 7 3 at high doses there is evidence of saturation of amine −17 bp of exon 9 1 activation [21,22 ]. Furthermore HAs are potently tumorigenic in neonatal B6C3F 1 mice at cumulative Mutations were determined by RT/PCR of total RNA.…”

PhIP metabolites in human urine after consumption of well-cooked chicken

“…N-hydroxy-PhIP can form stable glucuronide conjugates at the N 2 and N3 positions that can be excreted or transported to extrahepatic tissue for further metabolism [44,45]. 4 -Hydroxy-PhIP can be conjugated by sulfation and glucuronidation to polar compounds that are readily excreted [46,47]. In addition, the parent com- pound can be directly glucuronidated at the N 2 and N3 positions.…”

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

“…Although PhIP is less potent in the Salmonella test than the quinoline-and the quinoxaline-AIA compounds, it has been shown to be an equally potent genotoxin in mammalian cells both in vitro and in vivo (7)(8)(9)(10) in rats (11) and abdominal lymphomas in mice (12). In a series of previous studies, we have characterized the metabolic pathways of PhIP leading to mutagenic activation and detoxification (10,(13)(14)(15)(16). In these studies we have used whole rats, isolated rat hepatocytes, subcellular fractions, and purified enzymes.…”