title: Altered tissue distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA adducts in mice transgenic for human sulfotransferases 1A1 and 1A2.
abstract: Soluble sulfotransferases (SULTs) generate electrophilically reactive metabolites from numerous food-borne compounds, environmental contaminants and drugs, often resulting in mutagenicity and carcinogenicity. Substrate specificity, regulation and tissue distribution of SULTs show large interspecies differences. In humans, therefore, SULTs may be involved in the induction of cancer in different tissues than in standard animal models. To construct a rodent model taking some species differences into account, we transferred a 68.5 kb human (h) genomic sequence that comprised the transcribed and long flanking regions of SULT1A1 and 1A2 into murine oocytes. This approach resulted in several mouse lines expressing these human genes in a copy number-dependent manner with a tissue distribution similar to that in humans. In previous in vitro studies, we had demonstrated that human SULT1A1 and 1A2 efficiently catalyze the terminal activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to a mutagen. The transgenic mice were used to study the hSULT1A1/1A2-mediated activation. Tissue distribution and levels of DNA adducts were determined in hSULT1A1/1A2 transgenic and wild-type mice after an oral dosage of PhIP. Transgenic mice exhibited significantly elevated PhIP-DNA adduct levels compared with the wild-type in liver (13-fold), lung (3.8-fold), colon (2-fold), kidney (1.6-fold) and cecum (1.5-fold). Moreover, among the eight tissues examined, liver was the one with the lowest and highest adduct levels in wild-type and transgenic mice, respectively. Hence, expression of hSULT1A1/1A2 not only enhanced the genotoxicity but also substantially changed the organotropism of PhIP.
authors: German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Nutritional Toxicology, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors: Gisela
authors: G
authors: Dobbernack
authors: Walter
authors: W
authors: Meinl
authors: Nicole
authors: N
authors: Schade
authors: Simone
authors: S
authors: Florian
authors: Korinna
authors: K
authors: Wend
authors: Ingo
authors: I
authors: Voigt
authors: Heinz
authors: H
authors: Himmelbauer
authors: Madeleine
authors: M
authors: Gross
authors: Thomas
authors: T
authors: Liehr
authors: Hansruedi
authors: H
authors: Glatt
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000502:physiology*; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014018:Tissue Distribution
chemical_list: C502239:2-amino-1-methyl-6-phenolimidazo(4,5-b)pyridine-DNA adduct; D018736:DNA Adducts; D007093:Imidazoles; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C513290:SULT1A2 protein, human