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Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 12-25

Aristolochic acid-induced genotoxicity and toxicogenomic changes in rodents

1 Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, AR, USA
2 Tianjin Center for New Drug Safety Assessment and Research, Tianjin, China

Correspondence Address:
Dr. Nan Mei
3900 NCTR Road, Jefferson, AR 72079
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjtcm.wjtcm_33_19

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Aristolochic acid (AA) is a group of structurally related nitrophenanthrene carboxylic acids found in many plants that are widely used by many cultures as traditional herbal medicines. AA is a causative agent for Chinese herbs nephropathy, a term replaced later by AA nephropathy. Evidence indicates that AA is nephrotoxic, genotoxic, and carcinogenic in humans; and it also induces tumors in the forestomach, kidney, renal pelvis, urinary bladder, and lung of rats and mice. Therefore, plants containing AA have been classified as carcinogenic to humans (Group 1) by the International Agency for Research on Cancer. In our laboratories, we have conducted a series of genotoxicity and toxicogenomic studies in the rats exposed to AA of 0.1–10 mg/kg for 12 weeks. Our results demonstrated that AA treatments induced DNA adducts and mutations in the kidney, liver, and spleen of rats, as well as significant alteration of gene expression in both its target and nontarget tissues. AA treatments altered mutagenesis- or carcinogenesis-related microRNA expression in rat kidney and resulted in significant changes in protein expression profiling. We also applied benchmark dose (BMD) modeling to the 3-month AA-induced genotoxicity data. The obtained BMDL10(the lower 95% confidence interval of the BMD10that is a 10% increase over the background level) for AA-induced mutations in the kidney of rats was about 7 μg/kg body weight per day. This review constitutes an overview of our investigations on AA-induced genotoxicity and toxicogenomic changes including gene expression, microRNA expression, and proteomics; and presents updated information focused on AA-induced genotoxicity in rodents.

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