title: Human sulphotransferases are involved in the activation of aristolochic acids and are expressed in renal target tissue.
abstract: Use of herbal preparations containing Aristolochia species has led to progressive nephropathy and urothelial cancer in humans. Analysis of DNA adducts formed in human target tissues and studies in animal models have pointed out a major role of the secondary plant metabolites, aristolochic acids, in these effects. Only a minority of the users of Aristolochia-containing products developed nephropathy and cancer, suggesting differences in individual susceptibility. Differences in metabolic activation and inactivation frequently affect the susceptibility towards chemicals. Others have shown that the activation of aristolochic acids to DNA-reactive and mutagenic metabolites requires reduction of their aryl nitro group. The biological activity of numerous nitro- and aminoarenes, after appropriate phase I metabolism, is strongly enhanced in the presence of acetyltransferases or sulphotransferases (SULTs). In the present study, we demonstrate that expression of human SULTs in bacterial and mammalian target cells reinforces the mutagenic activity of aristolochic acids. Using Salmonella typhimurium TA1538 as the recipient organism, we identified the expression of all 12 human SULT forms. SULT1A1 led to the strongest increase in the mutagenicity of aristolochic acids. Some activation was also observed with SULT1B1, but not with the remaining forms. The role of SULT1A1 in the activation of aristolochic acids was corroborated using S. typhimurium TA100- and Chinese hamster V79-derived target cells engineered for expression of human SULT1A1 when compared with control cells. Furthermore, pentachlorophenol, an inhibitor of SULT1A1, strongly reduced the mutagenic effect of aristolochic acids in V79-hCYP2E1-hSULT1A1 cells. Moreover, we demonstrate that SULT1A1 and SULT1B1 are expressed in human kidney using immunoblot analysis, but their levels are substantially lower than in liver. Finally, we discuss the possibility that reactive sulphuric acid conjugates produced in other tissues are transferred to kidney and ureter.
authors.affiliation: Department of Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558 Nuthetal, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Meinl
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pabel
authors.forename: Mandy
authors.initials: M
authors.lastname: Osterloh-Quiroz
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
mesh_terms: D000368:Aged; D000818:Animals; D034341:Aristolochic Acids / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D016296:Mutagenesis / Q000235:genetics; D009928:Organ Specificity; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium / Q000235:genetics; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
chemical_list: D034341:Aristolochic Acids; D011994:Recombinant Proteins; D015238:Sulfotransferases