title: Detoxification of aristolochic acid I by O-demethylation: less nephrotoxicity and genotoxicity of aristolochic acid Ia in rodents.
abstract: Ingestion of aristolochic acids (AA) contained in herbal remedies results in aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA I and AA II, primary components in AA, have similar genotoxic potential, whereas only AA I shows severe renal toxicity in rodents. AA I is demethylated to form 8-hydroxy-aristolochic acid I (AA Ia) as a major metabolite. However, the nephrotoxicity and genotoxicity of AA Ia has not yet been determined. AA Ia was isolated from urine collected from rats treated with AA I and characterized by NMR and mass spectrometry. The purified AA Ia was administered intraperitoneally to C3H/He male mice for 9 days and its toxicity was compared with AA I. Using (32)P-postlabeling/polyacrylamide gel electrophoresis, the level of AA Ia-derived DNA adducts in renal cortex was approximately 70-110 times lower than that observed with AA I, indicating that AA Ia has only a limited genotoxicity. Supporting this result, when calf thymus DNA was reacted with AA Ia in a buffer containing zinc dust, the formation of AA Ia-DNA adducts was two-orders of magnitude lower than that of AA I. Histopathologic analysis revealed that unlike AA I, no significant changes were detected in the renal cortex of mice treated with AA Ia. Therefore, the contribution of AA Ia to renal toxicity is minimum. We conclude the metabolic pathway of converting AA I to AA Ia functions as the detoxification of AA I.
authors.affiliation: Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York, Stony Brook, NY, USA. shinya@pharm.stonybrook.edu
authors.forename: Shinya
authors.initials: S
authors.lastname: Shibutani
authors.forename: Radha R
authors.initials: RR
authors.lastname: Bonala
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenquist
authors.forename: Robert
authors.initials: R
authors.lastname: Rieger
authors.forename: Naomi
authors.initials: N
authors.lastname: Suzuki
authors.forename: Francis
authors.initials: F
authors.lastname: Johnson
authors.forename: Frederick
authors.initials: F
authors.lastname: Miller
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000302:isolation & purification / Q000633:toxicity* / Q000652:urine*; D002273:Carcinogens / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000235:genetics; D018736:DNA Adducts / Q000235:genetics*; D008658:Inactivation, Metabolic; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008745:Methylation; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D017208:Rats, Wistar
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; D004247:DNA; C427203:calf thymus DNA; C000228:aristolochic acid I