Received for publication January 9, 2007.
Revised March 20, 2007.
Accepted for publication March 26, 2007.

Selective Toxicity of Aristolochic Acids I and II

Abstract

Ingestion of herbal remedies containing aristolochic acids (AA) 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 intraperitoneally or orally, 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 renal cortex, medulla and bladder, we found similar levels of DNA adducts derived from AA-I and AA-II. However, in non-target 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-ll. 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, while both compounds are cytotoxic, AA-l is solely responsible for the nephrotoxicity associated with AAN.

Key words: chemical toxicology, DNA adducts, genotoxicity, renal toxicity