Co-Exposure to Aristolochic Acids I and II Increases DNA Adduct Formation Responsible for Aristolochic Acid I-Mediated Carcinogenicity in Rats
| Autor: | Marie Stiborová, Volker M. Arlt, Petr Hodek, Heinz H. Schmeiser, Michaela Bebová, Šárka Dušková, Jaroslav Mráz, František Bárta, Alena Dedı́ková |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Carcinogenesis cytochrome P450 QH301-705.5 aristolochic acid-mediated carcinogenesis Aristolochic acid Pharmacology medicine.disease_cause NAD(P)H:quinone oxidoreductase 1 Catalysis Article Adduct Inorganic Chemistry chemistry.chemical_compound In vivo medicine Animals Physical and Theoretical Chemistry Rats Wistar Biology (General) Molecular Biology QD1-999 Spectroscopy Carcinogen aristolochic acid I chemistry.chemical_classification biology Chemistry Organic Chemistry genotoxicity Balkan endemic nephropathy Cytochrome P450 DNA adducts General Medicine Metabolism DNA Neoplasm aristolochic acid II Computer Science Applications Rats Enzyme aristolochic acid nephropathy biology.protein Carcinogens Aristolochic Acids Genotoxicity |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 10479, p 10479 (2021) International Journal of Molecular Sciences Volume 22 Issue 19 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | The plant extract aristolochic acid (AA), containing aristolochic acids I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases associated with upper urothelial cancer. Recently (Chemical Research in Toxicology 33(11), 2804–2818, 2020), we showed that the in vivo metabolism of AAI and AAII in Wistar rats is influenced by their co-exposure (i.e., AAI/AAII mixture). Using the same rat model, we investigated how exposure to the AAI/AAII mixture can influence AAI and AAII DNA adduct formation (i.e., AA-mediated genotoxicity). Using 32P-postlabelling, we found that AA-DNA adduct formation was increased in the livers and kidneys of rats treated with AAI/AAII mixture compared to rats treated with AAI or AAII alone. Measuring the activity of enzymes involved in AA metabolism, we showed that enhanced AA-DNA adduct formation might be caused partially by both decreased AAI detoxification as a result of hepatic CYP2C11 inhibition during treatment with AAI/AAII mixture and by hepatic or renal NQO1 induction, the key enzyme predominantly activating AA to DNA adducts. Moreover, our results indicate that AAII might act as an inhibitor of AAI detoxification in vivo. Consequently, higher amounts of AAI might remain in liver and kidney tissues, which can be reductively activated, resulting in enhanced AAI DNA adduct formation. Collectively, these results indicate that AAII present in the plant extract AA enhances the genotoxic properties of AAI (i.e., AAI DNA adduct formation). As patients suffering from AAN and BEN are always exposed to the plant extract (i.e., AAI/AAII mixture), our findings are crucial to better understanding host factors critical for AAN- and BEN-associated urothelial malignancy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|