Selective toxicity of aristolochic acids I and II.
Ingestion of herbal remedies containing aristolochic acids (AAs) is associated with the development of a syndrome, designated aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis, and urothelial cancer. To distinguish the component(s) of AA responsible for these varied toxic effects, we administered 2.5 mg/kg/day of AA-I or AA-II for 9 days, either i.p. or p.o., to male C3H/He mice. Tissues were then collected and subjected to biochemical and histopathologic examination. Genotoxicity was assessed by determining quantitatively the level of aristolactam-DNA adducts in various tissues using (32)P-postlabeling/polyacrylamide gel electrophoresis and an internal standard. In the primary target tissues, represented by the renal cortex, medulla, and bladder, we found similar levels of DNA adducts derived from AA-I and AA-II. However, in nontarget tissues, the liver, stomach, intestine, and lung, the levels of aristolactam-DNA adducts derived from AA-I were significantly higher than those derived from AA-II. Histopathologic analysis revealed tubular cell necrosis and interstitial fibrosis in the renal cortex of AA-I-treated mice but only minimal changes in the renal cortex of mice treated with AA-II. We conclude that AA-I and AA-II have similar genotoxic and carcinogenic potential, and, although both compounds are cytotoxic, AA-I is solely responsible for the nephrotoxicity associated with AAN.
Shibutani
Shinya
S
Laboratory of Chemical Biology, Department of Pharmaceutical Sciences, State University of New York, Stony Brook, NY 11794-8651, USA. shinya@pharm.stonybrook.edu
Dong
Huan
H
Suzuki
Naomi
N
Ueda
Shiro
S
Miller
Frederick
F
Grollman
Arthur P
AP
D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D005355:Fibrosis; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009153:Mutagens / Q000633:toxicity*; D028321:Plant Preparations / Q000633:toxicity*; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism
D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; D028321:Plant Preparations; C000228:aristolochic acid I; C042310:aristolochic acid II