Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach
Aristolochic acid I (AAI) is a well-known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA-reactive aristolactam-nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI-DNA adduct formation in the kidney of rat, mouse and human...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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John Wiley & Sons
2020
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| Online Access: | http://psasir.upm.edu.my/id/eprint/88350/ http://psasir.upm.edu.my/id/eprint/88350/1/ABSTRACT.pdf |
| _version_ | 1848860601746456576 |
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| author | Abdullah, Rozaini Wesseling, Sebastiaan Spenkelink, Bert Louisse, Jochem Punt, Ans Rietjens, Ivonne M. C. M. |
| author_facet | Abdullah, Rozaini Wesseling, Sebastiaan Spenkelink, Bert Louisse, Jochem Punt, Ans Rietjens, Ivonne M. C. M. |
| author_sort | Abdullah, Rozaini |
| building | UPM Institutional Repository |
| collection | Online Access |
| description | Aristolochic acid I (AAI) is a well-known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA-reactive aristolactam-nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI-DNA adduct formation in the kidney of rat, mouse and human by translating the in vitro concentration-response curves for AAI-DNA adduct formation to the in vivo situation using physiologically based kinetic (PBK) modeling-based reverse dosimetry. DNA adduct formation in kidney proximal tubular LLC-PK1 cells exposed to AAI was quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. Subsequently, the in vitro concentration-response curves were converted to predicted in vivo dose-response curves in rat, mouse and human kidney using PBK models. Results obtained revealed a dose-dependent increase in AAI-DNA adduct formation in the rat, mouse and human kidney and the predicted DNA adduct levels were generally within an order of magnitude compared with values reported in the literature. It is concluded that the combined in vitro PBK modeling approach provides a novel way to define in vivo dose-response curves for kidney DNA adduct formation in rat, mouse and human and contributes to the reduction, refinement and replacement of animal testing. |
| first_indexed | 2025-11-15T12:47:50Z |
| format | Article |
| id | upm-88350 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T12:47:50Z |
| publishDate | 2020 |
| publisher | John Wiley & Sons |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-883502022-11-24T01:39:09Z http://psasir.upm.edu.my/id/eprint/88350/ Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach Abdullah, Rozaini Wesseling, Sebastiaan Spenkelink, Bert Louisse, Jochem Punt, Ans Rietjens, Ivonne M. C. M. Aristolochic acid I (AAI) is a well-known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA-reactive aristolactam-nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI-DNA adduct formation in the kidney of rat, mouse and human by translating the in vitro concentration-response curves for AAI-DNA adduct formation to the in vivo situation using physiologically based kinetic (PBK) modeling-based reverse dosimetry. DNA adduct formation in kidney proximal tubular LLC-PK1 cells exposed to AAI was quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. Subsequently, the in vitro concentration-response curves were converted to predicted in vivo dose-response curves in rat, mouse and human kidney using PBK models. Results obtained revealed a dose-dependent increase in AAI-DNA adduct formation in the rat, mouse and human kidney and the predicted DNA adduct levels were generally within an order of magnitude compared with values reported in the literature. It is concluded that the combined in vitro PBK modeling approach provides a novel way to define in vivo dose-response curves for kidney DNA adduct formation in rat, mouse and human and contributes to the reduction, refinement and replacement of animal testing. John Wiley & Sons 2020 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/88350/1/ABSTRACT.pdf Abdullah, Rozaini and Wesseling, Sebastiaan and Spenkelink, Bert and Louisse, Jochem and Punt, Ans and Rietjens, Ivonne M. C. M. (2020) Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach. Journal of Applied Toxicology, 40 (12). pp. 1647-1660. ISSN 1099-1263 https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/jat.4024 10.1002/jat.4024 |
| spellingShingle | Abdullah, Rozaini Wesseling, Sebastiaan Spenkelink, Bert Louisse, Jochem Punt, Ans Rietjens, Ivonne M. C. M. Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach |
| title | Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach |
| title_full | Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach |
| title_fullStr | Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach |
| title_full_unstemmed | Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach |
| title_short | Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach |
| title_sort | defining in vivo dose-response curves for kidney dna adduct formation of aristolochic acid i in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach |
| url | http://psasir.upm.edu.my/id/eprint/88350/ http://psasir.upm.edu.my/id/eprint/88350/ http://psasir.upm.edu.my/id/eprint/88350/ http://psasir.upm.edu.my/id/eprint/88350/1/ABSTRACT.pdf |