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Publication Detail

Title: Cytotoxicity and genotoxicity of the carcinogen aristolochic acid I (AA-I) in human bladder RT4 cells.

Authors: Bellamri, Medjda; Brandt, Kyle; Brown, Christina V; Wu, Ming-Tsang; Turesky, Robert J

Published In Arch Toxicol, (2021 06)

Abstract: Aristolochic acid (AA-I) induces upper urothelial tract cancer (UUTC) and bladder cancer (BC) in humans. AA-I forms the 7-(2'-deoxyadenosin-N6-yl)aristolactam I (dA-AL-I) adduct, which induces multiple A:T-to-T:A transversion mutations in TP53 of AA-I exposed UTUC patients. This mutation is rarely reported in TP53 of other transitional cell carcinomas and thus recognized as an AA-I mutational signature. A:T-to-T:A transversion mutations were recently detected in bladder tumors of patients in Asia with known AA-I-exposure, implying that AA-I contributes to BC. Mechanistic studies on AA-I genotoxicity have not been reported in human bladder. In this study, we examined AA-I DNA adduct formation and mechanisms of toxicity in the human RT4 bladder cell line. The biological potencies of AA-I were compared to 4-aminobiphenyl, a recognized human bladder carcinogen, and several structurally related carcinogenic heterocyclic aromatic amines (HAA), which are present in urine of smokers and omnivores. AA-I (0.05-10 µM) induced a concentration- and time-dependent cytotoxicity. AA-I (100 nM) DNA adduct formation occurred at over a thousand higher levels than the principal DNA adducts formed with 4-ABP or HAAs (1 µM). dA-AL-I adduct formation was detected down to a 1 nM concentration. Studies with selective chemical inhibitors provided evidence that NQO1 is the major enzyme involved in AA-I bio-activation in RT4 cells, whereas CYP1A1, another enzyme implicated in AA-I toxicity, had a lesser role in bio-activation or detoxification of AA-I. AA-I DNA damage also induced genotoxic stress leading to p53-dependent apoptosis. These biochemical data support the human mutation data and a role for AA-I in BC.

PubMed ID: 33938965 Exiting the NIEHS site

MeSH Terms: Aminobiphenyl Compounds/toxicity; Aristolochic Acids/administration & dosage; Aristolochic Acids/toxicity*; Carcinogens/administration & dosage; Carcinogens/toxicity*; Cell Line, Tumor; Cytochrome P-450 CYP1A1/metabolism; DNA Adducts/metabolism; DNA Damage/drug effects*; Dose-Response Relationship, Drug; Humans; Mutation; NAD(P)H Dehydrogenase (Quinone)/metabolism; Tumor Suppressor Protein p53/genetics; Urinary Bladder Neoplasms/pathology; Urinary Bladder/drug effects*; Urinary Bladder/pathology

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