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.

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

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

Department of Biochemistry Faculty of Science Charles University Albertov 2030 12840 Prague 2 Czech Republic

Department of Nutritional Toxicology German Institute of Human Nutrition 10589 Berlin Germany

Department of Nutritional Toxicology German Institute of Human Nutrition Potsdam Rehbrücke 14558 Nuthetal Germany

Division of Cancer Therapeutics Institute of Cancer Research Sutton Surrey SM2 5NG UK

Division of Radiopharmaceutical Chemistry German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

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$a Arlt, Volker M. $u 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. $7 xx0074763 $4

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$a Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone / $c VM. Arlt, W. Meinl, S. Florian, E. Nagy, F. Barta, M. Thomann, I. Mrizova, AM. Krais, M. Liu, M. Richards, A. Mirza, K. Kopka, DH. Phillips, H. Glatt, M. Stiborova, HH. Schmeiser,

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$a 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.

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$a Meinl, Walter $u Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558, Nuthetal, Germany.

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$a Florian, Simone $u Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558, Nuthetal, Germany.

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$a Nagy, Eszter $u 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.

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$a Barta, Frantisek $u Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840, Prague 2, Czech Republic.

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$a Thomann, Marlies $u 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.

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$a Mrizova, Iveta $u Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840, Prague 2, Czech Republic.

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$a Krais, Annette M $u 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.

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$a Liu, Maggie $u Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.

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$a Richards, Meirion $u Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.

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$a Mirza, Amin $u Division of Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.

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$a Kopka, Klaus $u Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

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$a Phillips, David H $u 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.

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$a Glatt, Hansruedi $u 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.

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$a Stiborova, Marie $u Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840, Prague 2, Czech Republic.

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$a Schmeiser, Heinz H $u Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

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