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Drug Metabolism and Disposition Fast Forward
First published on April 12, 2006; DOI: 10.1124/dmd.105.008706

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Received for publication December 1, 2005.
Revised March 27, 2006.
Accepted for publication April 5, 2006.

Quantitative determination of aristolochic acid-derived DNA adducts in rats using 32P-postlabeling/PAGE analysis

Huan Dong 1, Naomi Suzuki 1, Maria C. Torres 1, Radha R. Bonala 1, Francis Johnson 1, Arthur P. Grollman 1, Shinya Shibutani 1*

1 State University of New York at Stony Brook

* Address correspondence to: E-mail: shinya{at}pharm.stonybrook.edu

Abstract

Aristolochic acids (AA) are nephrotoxic and carcinogenic nitroaromatic compounds produced by the Aristolochiaceae family of plants. Ingestion of these phytotoxins by humans results in a syndrome known as aristolochic acid nephropathy, characterized by renal tubulointerstitial fibrosis and upper urothelial cancer. Following activation by cellular enzymes, aristolochic acids l and ll react with DNA to form covalent adducts and, as such, represent potential biomarkers for studies of AA toxicity. Using site-specifically modified oligodeoxynucleotides as standards, we have developed a method for quantifying dA-AA- or dG-AA-DNA adducts in tissues of Wistar rats using an assay in which 32P-postlabeling techniques are coupled with nondenaturing polyacrylamide gel electrophoresis. The limit of detection with this technique is 5 adducts in 109 nucleotides for a 5 µg DNA sample. In contrast to previous reports, we find that the levels of AA adducts in renal tissues of Wistar rats treated orally with AA for one week with 5 mg/kg/day of AA I or AA ll were much higher than that in the forestomach. Highest adduct levels were observed in rats treated with AA II, suggesting that this compound may be more genotoxic than AA I. Treatment of rats with aristolactam I, an end product of AA l metabolism, resulted in a much lower level of adduction. This study establishes the feasibility of using AA-DNA adducts as intermediate biomarkers of exposure in studies of aristolochic acid nephropathy and its associated urothelial cancer.


Key words: chemical carcinogenesis, DNA adducts, renal toxicity


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