Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5'-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes
| العنوان: | Mertansine Inhibits mRNA Expression and Enzyme Activities of Cytochrome P450s and Uridine 5'-Diphospho-Glucuronosyltransferases in Human Hepatocytes and Liver Microsomes |
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| المؤلفون: | Yongho Shin, Hye Suk Lee, Won-Gu Choi, Dong Kyun Kim, Ria Park, Yong-Yeon Cho |
| المصدر: | Pharmaceutics Pharmaceutics, Vol 12, Iss 3, p 220 (2020) Volume 12 Issue 3 |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | CYP2B6, cytochrome P450, Glucuronidation, Pharmaceutical Science, lcsh:RS1-441, macromolecular substances, Pharmacology, Mertansine, 030226 pharmacology & pharmacy, Article, lcsh:Pharmacy and materia medica, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, drug–drug interaction, biology, CYP3A4, CYP1A2, human hepatocytes, Cytochrome P450, UGT2B7, chemistry, 030220 oncology & carcinogenesis, Microsome, biology.protein, UDP-glucuronosyltransferases, mertansine |
| الوصف: | Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody&ndash drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5&prime diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug&ndash drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-&beta glucuronidation, and UGT1A4-catalyzed trifluoperazine N-&beta d-glucuronidation, with Ki values of 13.5 µ M, 4.3 µ M, and 21.2 µ M, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25&ndash 2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC50 values of 93.7 109.1, 36.8 18.3, 160.6 167.4, 32.1 14.9, 578.4 452.0, 539.5 233.4, 856.7 781.9, and 54.1 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin O-deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic. |
| وصف الملف: | application/pdf |
| تدمد: | 1999-4923 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a5c78e0dfc53e744a7ac83b6267b86f https://pubmed.ncbi.nlm.nih.gov/32131538 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....9a5c78e0dfc53e744a7ac83b6267b86f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19994923 |
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