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Drug Metabolism and Disposition Fast Forward
First published on March 28, 2007; DOI: 10.1124/dmd.107.014688

0090-9556/07/3507-1217-1222$20.00
DMD 35:1217-1222, 2007

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Selective Toxicity of Aristolochic Acids I and II

Shinya Shibutani, Huan Dong, Naomi Suzuki, Shiro Ueda, Frederick Miller, and Arthur P. Grollman

Laboratory of Chemical Biology, Department of Pharmacological Sciences (S.S., H.D., N.S., A.P.G.) and Department of Pathology (F.M.), State University of New York, Stony Brook, New York; and Department of Drug Information and Communication, Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba, Japan (S.U.)

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 32P-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.

Address correspondence to: Dr. Shinya Shibutani, 1 Nicolls Road, Stony Brook, NY 11794-8651. E-mail: shinya{at}pharm.stonybrook.edu




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