The identification of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine metabolites in humans

• Published in: Carcinogenesis (New York) 1999-04, Vol.20 (4), p.705-713
• Main Authors: Malfatti, Michael A., Kulp, Kristen S., Knize, Mark G., Davis, Cindy, Massengill, Joyce P., Williams, Suzanne, Nowell, Susan, MacLeod, Stewart, Dingley, Karen H., Turteltaub, Kenneth W., Lang, Nicholas P., Felton, James S.
• Format: Article
• Language: English
• Subjects: 2-amino-1-methyl-6-(4′-hydroxy)phenylimidazo; 2-amino-1-methyl-6-phenylimidazo; 2-hydroxyamino-1-methyl-6-phenylimidazo; 4′-(2-amino-1-methylimidazo; 4′-hydroxy-PhIP; 4′-PhIP-sulfate; 5-b]pyrid-6-yl) phenyl sulfate; 5-b]pyridine; Administration, Oral; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Biotransformation; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - administration & dosage; Carcinogens - analysis; Carcinogens - pharmacokinetics; Chemical agents; Chromatography, High Pressure Liquid; CID; collision induced dissociation; Colonic Neoplasms - metabolism; CYP1A2; Cytochrome P-450 CYP1A2 - genetics; Cytochrome P-450 CYP1A2 - metabolism; cytochrome P4501A2; Dogs; Glucuronates - urine; heterocyclic amine; Hot Temperature; Humans; Imidazoles - administration & dosage; Imidazoles - blood; Imidazoles - pharmacokinetics; Imidazoles - urine; Male; Meat; Medical sciences; Mice; Microsomes, Liver - enzymology; Molecular Structure; N-acetyltransferase; N-hydroxy-PhIP; NAT2; Phenotype; PhIP; retention time; Species Specificity; sulfotransferase; Tumors; UDP–glucuronosyltransferase; UDP–GT
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/20.4.705

[2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ([14C]PhIP), a putative human carcinogenic heterocyclic amine found in well-done cooked meat, was administered orally to three colon cancer patients undergoing a partial colonectomy. Forty-eight to seventy-two hours prior to surgery, subjects received a 70–84 μg dose of 14C. Urine and blood were analyzed by HPLC for PhIP and PhIP metabolites. Metabolites were identified based on HPLC co-elution with authentic PhIP metabolite standards, mass spectral analysis and susceptibility to enzymatic cleavage. In two subjects, ~90% of the administered [14C]PhIP dose was eliminated in the urine, whereas in the other, only 50% of the dose was found in the urine. One subject excreted three times more radioactivity in the first 4 h than did the others. Twelve radioactive peaks associated with PhIP were detected in the urine samples. The relative amount of each metabolite varied by subject, and the amounts of each metabolite within subjects changed over time. In all three subjects the most abundant urinary metabolite was identified as 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine-N2-glucuronide (N-hydroxy-PhIP-N2-glucuronide), accounting for 47–60% of the recovered counts in 24 h. PhIP accounted for