Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis.

F. Kadlubar, R. K. Kaderlik, G. J. Mulder, D. Lin, M. A. Butler, C. H. Teitel, R. F. Minchin, K. F. Ilett, M. D. Friesen, H. Bartsch

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

The metabolic activation of the heterocyclic amine carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was examined in dogs and rats as models for urinary bladder and colon carcinogenesis, respectively. The results indicate that unconjugated N-OH-PhIP is not excreted in the urine after oral dosing with PhIP and that the two isomeric N-glucuronides of N-OH-PhIP, which are formed as major metabolites, are stable under acidic conditions. These data suggest that PhIP is unlikely to serve as a urinary bladder carcinogen in either species. Using metabolic inhibitors, bile duct ligation, and intravenous dosing studies, a new hypothesis for colorectal carcinogenesis is proposed involving N-oxidation of PhIP by hepatic cytochrome P-4501A2 (CYP1A2) and O-acetylation by the polymorphic acetyltransferase (NAT2). The resulting N-hydroxy and N-acetoxy metabolites both appear to be transported through the circulation to the colon mucosa, forming covalent DNA adducts. Glucuronidation and reaction with glutathione appear to serve as detoxification pathways. In humans, individuals who are phenotypically rapid metabolizers for both CYP1A2 and NAT2 are significantly higher (p = 0.0015) in colorectal cancer/poly cases vs. controls; and PhIP-DNA adducts can be detected in human colon samples. These studies provide strong evidence that PhIP and other heterocyclic amines play an important role in the etiology of human colorectal cancer.

Original languageEnglish (US)
Title of host publicationPrincess Takamatsu symposia
Pages207-213
Number of pages7
Volume23
StatePublished - 1995
Externally publishedYes

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Colon
Carcinogenesis
Urinary Bladder
Dogs
Cytochromes
Carcinogens
Amines
Colorectal Neoplasms
Acetyltransferases
DNA Adducts
Glucuronides
Acetylation
Bile Ducts
Glutathione
Ligation
Metabolic Activation
2-amino-1-methyl-6-phenolimidazo(4,5-b)pyridine-DNA adduct
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
Mucous Membrane
Urine

Cite this

Kadlubar, F., Kaderlik, R. K., Mulder, G. J., Lin, D., Butler, M. A., Teitel, C. H., ... Bartsch, H. (1995). Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis. In Princess Takamatsu symposia (Vol. 23, pp. 207-213)

Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis. / Kadlubar, F.; Kaderlik, R. K.; Mulder, G. J.; Lin, D.; Butler, M. A.; Teitel, C. H.; Minchin, R. F.; Ilett, K. F.; Friesen, M. D.; Bartsch, H.

Princess Takamatsu symposia. Vol. 23 1995. p. 207-213.

Research output: Chapter in Book/Report/Conference proceedingChapter

Kadlubar, F, Kaderlik, RK, Mulder, GJ, Lin, D, Butler, MA, Teitel, CH, Minchin, RF, Ilett, KF, Friesen, MD & Bartsch, H 1995, Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis. in Princess Takamatsu symposia. vol. 23, pp. 207-213.
Kadlubar F, Kaderlik RK, Mulder GJ, Lin D, Butler MA, Teitel CH et al. Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis. In Princess Takamatsu symposia. Vol. 23. 1995. p. 207-213
Kadlubar, F. ; Kaderlik, R. K. ; Mulder, G. J. ; Lin, D. ; Butler, M. A. ; Teitel, C. H. ; Minchin, R. F. ; Ilett, K. F. ; Friesen, M. D. ; Bartsch, H. / Metabolic activation and DNA adduct detection of PhIP in dogs, rats, and humans in relation to urinary bladder and colon carcinogenesis. Princess Takamatsu symposia. Vol. 23 1995. pp. 207-213
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abstract = "The metabolic activation of the heterocyclic amine carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was examined in dogs and rats as models for urinary bladder and colon carcinogenesis, respectively. The results indicate that unconjugated N-OH-PhIP is not excreted in the urine after oral dosing with PhIP and that the two isomeric N-glucuronides of N-OH-PhIP, which are formed as major metabolites, are stable under acidic conditions. These data suggest that PhIP is unlikely to serve as a urinary bladder carcinogen in either species. Using metabolic inhibitors, bile duct ligation, and intravenous dosing studies, a new hypothesis for colorectal carcinogenesis is proposed involving N-oxidation of PhIP by hepatic cytochrome P-4501A2 (CYP1A2) and O-acetylation by the polymorphic acetyltransferase (NAT2). The resulting N-hydroxy and N-acetoxy metabolites both appear to be transported through the circulation to the colon mucosa, forming covalent DNA adducts. Glucuronidation and reaction with glutathione appear to serve as detoxification pathways. In humans, individuals who are phenotypically rapid metabolizers for both CYP1A2 and NAT2 are significantly higher (p = 0.0015) in colorectal cancer/poly cases vs. controls; and PhIP-DNA adducts can be detected in human colon samples. These studies provide strong evidence that PhIP and other heterocyclic amines play an important role in the etiology of human colorectal cancer.",
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AU - Kaderlik, R. K.

AU - Mulder, G. J.

AU - Lin, D.

AU - Butler, M. A.

AU - Teitel, C. H.

AU - Minchin, R. F.

AU - Ilett, K. F.

AU - Friesen, M. D.

AU - Bartsch, H.

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N2 - The metabolic activation of the heterocyclic amine carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), was examined in dogs and rats as models for urinary bladder and colon carcinogenesis, respectively. The results indicate that unconjugated N-OH-PhIP is not excreted in the urine after oral dosing with PhIP and that the two isomeric N-glucuronides of N-OH-PhIP, which are formed as major metabolites, are stable under acidic conditions. These data suggest that PhIP is unlikely to serve as a urinary bladder carcinogen in either species. Using metabolic inhibitors, bile duct ligation, and intravenous dosing studies, a new hypothesis for colorectal carcinogenesis is proposed involving N-oxidation of PhIP by hepatic cytochrome P-4501A2 (CYP1A2) and O-acetylation by the polymorphic acetyltransferase (NAT2). The resulting N-hydroxy and N-acetoxy metabolites both appear to be transported through the circulation to the colon mucosa, forming covalent DNA adducts. Glucuronidation and reaction with glutathione appear to serve as detoxification pathways. In humans, individuals who are phenotypically rapid metabolizers for both CYP1A2 and NAT2 are significantly higher (p = 0.0015) in colorectal cancer/poly cases vs. controls; and PhIP-DNA adducts can be detected in human colon samples. These studies provide strong evidence that PhIP and other heterocyclic amines play an important role in the etiology of human colorectal cancer.

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