title: Bioactivation of the human carcinogen aristolochic acid.
abstract: Aristolochic acids are potent human carcinogens; the role of phase II metabolism in their bioactivation is unclear. Accordingly, we tested the ability of the partially reduced metabolites, N-hydroxyaristolactams (AL-NOHs), and their N-O-sulfonated and N-O-acetylated derivatives to react with DNA to form aristolactam-DNA adducts. AL-NOHs displayed little or no activity in this regard while the sulfo- and acetyl compounds readily form DNA adducts, as detected by (32)P-post-labeling analysis. Mouse hepatic and renal cytosols stimulated binding of AL-NOHs to DNA in the presence of adenosine 3'-phosphate 5'-phosphosulfate (PAPS) but not of acetyl-CoA. Using Time of Flight liquid chromatography/mass spectrometry, N-hydroxyaristolactam I formed the sulfated compound in the presence of PAPS and certain human sulfotransferases, SULT1B1 >>> SULT1A2 > SULT1A1 >>> SULT1A3. The same pattern of SULT reactivity was observed when N-hydroxyaristolactam I was incubated with these enzymes and PAPS and the reaction was monitored by formation of aristolactam-DNA adducts. In the presence of human
  quinone oxidoreductase, the ability of aristolochic acid I to bind DNA covalently was increased significantly by addition of PAPS and SULT1B1. We conclude from these studies that AL-NOHs, formed following partial nitroreduction of aristolochic acids, serve as substrates for SULT1B1, producing N-sulfated esters, which, in turn, are converted to highly active species that react with DNA and, potentially, cellular proteins, resulting in the genotoxicity and nephrotoxicity associated with ingestion of aristolochic acids by humans.
authors.affiliation: Department of Pharmacological Sciences, viktoriya.sidorenko@stonybrook.edu.
authors.forename: Viktoriya S
authors.initials: VS
authors.lastname: Sidorenko
authors.affiliation: Department of Pharmacological Sciences.
authors.forename: Sivaprasad
authors.initials: S
authors.lastname: Attaluri
authors.affiliation: Department of Pharmacological Sciences.
authors.forename: Irina
authors.initials: I
authors.lastname: Zaitseva
authors.affiliation: Department of Pharmacological Sciences.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Iden
authors.affiliation: Department of Pharmacological Sciences, Department of Medicine and.
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Dickman
authors.affiliation: Department of Pharmacological Sciences, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Johnson
authors.affiliation: Department of Pharmacological Sciences, Department of Medicine and.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000494:pharmacology*; D015239:Arylsulfotransferase / Q000378:metabolism; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism; D004983:Ethanolamines; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008958:Models, Molecular; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013229:Stearic Acids; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; D004983:Ethanolamines; C408368:N-stearoylethanolamine; D013229:Stearic Acids; C000228:aristolochic acid I; D010088:Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C052449:3'-phosphoadenylyl-5'-phosphosulfate reductase; D015238:Sulfotransferases; C109377:iodothyronine sulfotransferase; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C513290:SULT1A2 protein, human; C403170:monoamine-sulfating phenol sulfotransferase
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