title: Identification of a reduction product of aristolochic acid: implications for the metabolic activation of carcinogenic aristolochic acid.
abstract: Aristolochic acids are nephrotoxic and carcinogenic natural products that have been implicated both in endemic nephropathy in the Balkan region and in ailments caused by ingestion of herbal remedies. Aristolochic acids are metabolized to active intermediates that bind to DNA. In this study, reduction of aristolochic acid I with zinc in acetic acid afforded a new product that was characterized as 9-methoxy-7-methyl-2H-1,3-oxazolo[5',4'-10,9]phenanthro[3,4-d]-1,3-dioxolane-5-carboxylic acid, designated as aristoxazole, along with the expected aristolactam I. This new compound is a condensation product of aristolochic acid and acetic acid that may be related to the aristolochic acid-DNA adducts. The proposed mechanism of formation of aristoxazole involves nucleophilic attack of acetic acid on the nitrenium ion of aristolochic acid I. On the basis of these studies, a route to the metabolic activation of aristolochic acids and formation of adducts with DNA in in vitro systems is proposed and discussed.
authors.affiliation: Department of Biological Sciences, Florida International University, 11200 Southwest 8th Street, Miami, FL 33199, USA. Priestap@fiu.edu
authors.forename: Horacio A
authors.initials: HA
authors.lastname: Priestap
authors.forename: Carlos
authors.initials: C
authors.lastname: de los Santos
authors.forename: J Martin E
authors.initials: JM
authors.lastname: Quirke
mesh_terms: D019342:Acetic Acid / Q000737:chemistry / Q000378:metabolism; D034341:Aristolochic Acids / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D029001:Herbal Medicine; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010080:Oxazoles / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; D010080:Oxazoles; C555177:aristoxazole; C000228:aristolochic acid I; D019342:Acetic Acid