Abstract
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.
Footnotes
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This research was supported by the Catacosinos Cancer Scholar Award from the School of Medicine, SUNY Stony Brook and Grant ES04068 from the National Institutes of Environmental Health Sciences.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.014688.
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ABBREVIATIONS: AA, aristolochic acid; AAN, aristolochic acid nephropathy; AA-I, aristolochic acid I, 8-methoxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid; AA-II, aristolochic acid II, 6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid; dA-AL, 7-(deoxyadenosin-N6-yl) aristolactam; dG-AL, 7-(deoxyguanosin-N2-yl) aristolactam; AL, aristolactam; PAGE, polyacrylamide gel electrophoresis.
- Received January 5, 2007.
- Accepted March 26, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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