title: Pancreatic DNA adducts formed in vitro and in vivo by the food mutagens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alphaC).
abstract: Genotoxic heterocyclic amines have been detected in grilled or fried meat and tobacco smoke. Among these, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alphaC) have been shown to induce tumours in rodents in several organs. Here we report on the DNA adduct formation by PhIP and MeA alphaC in vitro and in vivo, both in rat hepatic and rat pancreatic tissues or cells. Using 32P-postlabelling analysis both compounds were shown to induce a dose-dependent DNA modification in primary rat hepatocytes that was correlated with cytotoxicity in these cells. In explanted rat pancreas maintained in dynamic short-term organ culture MeA alphaC was shown to induce covalent DNA adducts. No DNA adducts were observed with PhIP in this assay. DNA adducts were observed in the liver and the pancreas of F344 rats treated with PhIP, with a 36-times higher level of adducts in the pancreas, confirming data reported earlier. DNA adduct levels induced by feeding 32, 160 or 800 ppm MeA alphaC in the diet were dose-dependent and higher in the liver compared with other organs including pancreas. While for PhIP the N2-(desoxyguanin-8-yl)-derivative was accounting for more than 90% of DNA adducts detected, in the case of MeA alphaC the N2-(desoxyguanin-8-yl) adduct was predominant in vitro and determined in vivo as one of up to 5 DNA adducts. MeA alphaC had been reported to induce preneoplastic foci and tumours in the liver and tumours and atrophy in the pancreas. In the case of MeA alphaC, the DNA adduct formation and cytotoxicity observed by us in vitro and in vivo correlate with the organ specificity of the reported pathological lesions. In the case of PhIP our in vitro data in pancreas and liver and the low adduct levels in liver in vivo also reflect the reported lack of pathological effects in these organs. In contrast, in pancreas, in vivo extraordinarily high adduct levels induced by PhIP were observed confirming studies published earlier, in spite of the fact that this compound does not cause pancreatic lesions. This enigmatic observation is discussed and the relevant literature is reviewed.
authors.affiliation: Department of Toxicology and Environmental Medicine of the Fraunhofer Society, Hamburg University Medical School, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Pfau
authors.forename: U
authors.initials: U
authors.lastname: Brockstedt
authors.forename: T
authors.initials: T
authors.lastname: Shirai
authors.forename: N
authors.initials: N
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Marquardt
mesh_terms: D000818:Animals; D002243:Carbolines / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism*; D004032:Diet; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009924:Organ Culture Techniques; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010761:Phosphorus Radioisotopes / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar
chemical_list: D002243:Carbolines; D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D009153:Mutagens; D010761:Phosphorus Radioisotopes; C017821:2-amino-3-methyl-9H-pyrido(2,3-b)indole; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine