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Structure-Guided Identification of Phytochemical OCT2 Inhibitors and Their Functional Relevance to Cisplatin-Induced
Hyerim Song1, Kyeong-Ryoon Lee2,3, Hui Li1
1College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea.
Abstract:
Background: Organic cation transporter 2 (OCT2) mediates the renal uptake of cisplatin and is a principal contributor to its dose-limiting nephrotoxicity. Despite reports of OCT2 inhibition by various phytochemicals, the structure-activity relationships (SARs) governing inhibition and their functional implications remain poorly understood. Methods: We systematically evaluated OCT2 inhibitory activity across a structurally diverse library of 146 phytochemicals, including anthraquinones, flavanols, stilbenes, and isoflavones, using Madin-Darby canine kidney (MDCK) cells stably overexpressing OCT2. Structure-activity relationships were analyzed using non-parametric statistics and multivariate logistic regression, and functional relevance was assessed via cisplatin-induced cytotoxicity assays. Results: Inhibitory activity varied widely across the library, with potent inhibitors identified across multiple chemical scaffolds. Non-parametric statistical analyses revealed no significant differences in overall activity distributions among scaffold classes. Notably, chemical substituent patterns, rather than core scaffold identity, were the primary drivers of OCT2 inhibitory potency. Methoxylation was consistently associated with enhanced OCT2 inhibition, particularly within isoflavones, although its impact varied across structural scaffolds. The selected OCT2 inhibitors markedly reduced cisplatin-mediated cell death in OCT2-expressing cells but not in mock-transfected controls, confirming an OCT2-dependent mechanism of protection. Conclusions: This study establishes a structure-guided framework linking phytochemical OCT2 inhibition to nephroprotective potential and identifies methoxylation as a major determinant of OCT2-targeted intervention strategies.
Insights
Phytochemicals can inhibit organic cation transporter 2 (OCT2), reducing cisplatin nephrotoxicity. Methoxylation is key for this protective effect, guiding the development of OCT2-targeted therapies.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Toxicology
Background:
- Organic cation transporter 2 (OCT2) is crucial for cisplatin uptake in kidneys, leading to nephrotoxicity.
- Understanding phytochemical inhibition of OCT2 is vital for mitigating this side effect.
- Structure-activity relationships (SARs) of phytochemical OCT2 inhibitors are not well-defined.
Purpose of the Study:
- To systematically evaluate OCT2 inhibitory activity of diverse phytochemicals.
- To elucidate the SARs governing OCT2 inhibition by phytochemicals.
- To assess the functional relevance of phytochemical OCT2 inhibition in preventing cisplatin nephrotoxicity.
Main Methods:
- Screened 146 phytochemicals for OCT2 inhibition using OCT2-overexpressing MDCK cells.
- Analyzed SARs using non-parametric statistics and multivariate logistic regression.
- Assessed functional impact via cisplatin-induced cytotoxicity assays.
Main Results:
- Potent OCT2 inhibitors were found across various chemical scaffolds.
- Chemical substituent patterns, especially methoxylation, significantly influenced inhibitory potency.
- Identified OCT2 inhibitors reduced cisplatin-induced cell death in an OCT2-dependent manner.
Conclusions:
- Established a structure-guided framework for phytochemical OCT2 inhibition.
- Methoxylation is a key determinant for OCT2-targeted nephroprotective strategies.
- Phytochemical OCT2 inhibition offers potential for mitigating cisplatin nephrotoxicity.
