Journal Article

Altered tissue distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-<i>b</i>]pyridine-DNA adducts in mice transgenic for human sulfotransferases 1A1 and 1A2

Gisela Dobbernack, Walter Meinl, Nicole Schade, Simone Florian, Korinna Wend, Ingo Voigt, Heinz Himmelbauer, Madeleine Gross, Thomas Liehr and Hansruedi Glatt

in Carcinogenesis

Volume 32, issue 11, pages 1734-1740
Published in print November 2011 | ISSN: 0143-3334
Published online September 2011 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgr204
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

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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.

Journal Article.  5983 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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