Abstract
Metabolism of the food-derived heterocyclic amine mutagen/carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was examined in cynomolgus monkeys. [3H]PhIP (50 μmol/kg, p.o.) was extensively metabolized, with only 1% of the dose excreted into the urine as parent compound. Four metabolites were isolated by HPLC and identified: PhIP-4′-O-glucuronide, PhIP-4′-sulfate, 4′-hydroxy-PhIP and a glucuronide conjugate of N-hydroxy-PhIP. All four metabolites were detected in urine, bile and plasma of monkeys. 4′-Hydroxy-PhIP and PhIP were found in feces. The major PhIP metabolite in urine, bile and plasma was PhIP-4′-sulfate. In urine this metabolite constituted ∼64-72% of the radioactivity excreted. The clearance of PhIP and PhIP metabolites from plasma was rapid, with the largest elimination occurring within 8 h. Administration of nine consecutive daily doses of unlabeled PhIP (50 μmol/kg, p.o.) prior to administration of [3H]PhIP (50 μmol/kg, p.o.) did not alter the plasma clearance of radiolabeled PhIP or PhIP metabolites, suggesting that this multiple-dose regimen did not induce or alter PhIP metabolism. PhIP formed DNA adducts in white blood cells, as determined by the 32P-postlabeling method. The levels of PhIP-DNA adducts in blood appeared to peak 3 h after administering a single dose of PhIP (50 μmol/kg, p.o.) and were still detected 1 week after dosing. The presence of the glucuronide conjugate of N-hydroxy-PhIP in urine, bile and plasma, and the presence of PnIP-DNA adducts in white blood cells indicate that PhIP undergoes metabolic activation via N-hydroxylation in cynomolgus monkeys. The results suggest that PhIP is activated in vivo to genotoxic metabolites in nonhuman primates and thus is a potential carcinogen in this species.
Original language | English (US) |
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Pages (from-to) | 2517-2522 |
Number of pages | 6 |
Journal | Carcinogenesis |
Volume | 14 |
Issue number | 12 |
State | Published - Dec 1993 |
Externally published | Yes |
ASJC Scopus subject areas
- Cancer Research
- Statistics, Probability and Uncertainty
- Applied Mathematics
- Physiology (medical)
- Physiology
- Behavioral Neuroscience