title: Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone.
abstract: Exposure to aristolochic acid (AA) causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). Conflicting results have been found for the role of human sulfotransferase 1A1 (SULT1A1) contributing to the metabolic activation of aristolochic acid I (AAI) in vitro. We evaluated the role of human SULT1A1 in AA bioactivation in vivo after treatment of transgenic mice carrying a functional human SULT1A1-SULT1A2 gene cluster (i.e. hSULT1A1/2 mice) and Sult1a1(-/-) mice with AAI and aristolochic acid II (AAII). Both compounds formed characteristic DNA adducts in the intact mouse and in cytosolic incubations in vitro. However, we did not find differences in AAI-/AAII-DNA adduct levels between hSULT1A1/2 and wild-type (WT) mice in all tissues analysed including kidney and liver despite strong enhancement of sulfotransferase activity in both kidney and liver of hSULT1A1/2 mice relative to WT, kidney and liver being major organs involved in AA metabolism. In contrast, DNA adduct formation was strongly increased in hSULT1A1/2 mice compared to WT after treatment with 3-nitrobenzanthrone (3-NBA), another carcinogenic aromatic nitro compound where human SULT1A1/2 is known to contribute to genotoxicity. We found no differences in AAI-/AAII-DNA adduct formation in Sult1a1(-/-) and WT mice in vivo. Using renal and hepatic cytosolic fractions of hSULT1A1/2, Sult1a1(-/-) and WT mice, we investigated AAI-DNA adduct formation in vitro but failed to find a contribution of human SULT1A1/2 or murine Sult1a1 to AAI bioactivation. Our results indicate that sulfo-conjugation catalysed by human SULT1A1 does not play a role in the activation pathways of AAI and AAII in vivo, but is important in 3-NBA bioactivation.
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK. volker.arlt@kcl.ac.uk.
authors.forename: Volker M
authors.identifier: http://orcid.org/0000-0003-4314-9318
authors.initials: VM
authors.lastname: Arlt
authors.affiliation: Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558, Nuthetal, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Meinl
authors.affiliation: Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558, Nuthetal, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Florian
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: Eszter
authors.initials: E
authors.lastname: Nagy
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840, Prague 2, Czech Republic.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Barta
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: Marlies
authors.initials: M
authors.lastname: Thomann
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840, Prague 2, Czech Republic.
authors.forename: Iveta
authors.initials: I
authors.lastname: Mrizova
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.|Division of Occupational and Environmental Medicine, Lund University, 221 85, Lund, Sweden.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Krais
authors.affiliation: Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Maggie
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Meirion
authors.initials: M
authors.lastname: Richards
authors.affiliation: Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.
authors.forename: Amin
authors.initials: A
authors.lastname: Mirza
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.affiliation: Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.affiliation: Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558, Nuthetal, Germany.|Department of Food Safety, Federal Institute for Risk Assessment (BfR), 10589, Berlin, Germany.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840, Prague 2, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborova
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D015239:Arylsulfotransferase / Q000235:genetics*; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D005810:Multigene Family
chemical_list: D034341:Aristolochic Acids; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D018736:DNA Adducts; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C513290:SULT1A2 protein, human; C117220:3-nitrobenzanthrone
keywords: 3-Nitrobenzanthrone; Aristolochic acid nephropathy; Balkan endemic nephropathy; Carcinogen metabolism; DNA adducts; Sulfotransferase 1A1