Prediction of seriniquinone-drug interactions by in vitro inhibition of human cytochrome P450 enzymes
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2020-06-01
Autores
Moreira da Silva, Rodrigo
Carrão, Daniel Blascke
Habenschus, Maísa Daniela
Jimenez, Paula Christine
Lopes, Norberto Peporine
Fenical, William
Costa-Lotufo, Letícia Vera
de Oliveira, Anderson Rodrigo Moraes [UNESP]
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Resumo
Seriniquinone is a secondary metabolite isolated from a rare marine bacterium of the genus Serinicoccus. This natural quinone is highlighted for its selective cytotoxic activity toward melanoma cancer cells, in which rapid metastatic properties are still a challenge for clinical treatment of malignant melanoma. The progress of seriniquinone as a promising bioactive molecule for drug development requires the assessment of its clinical interaction potential with other drugs. This study aimed to investigate the in vitro inhibitory effects of seriniquinone on the main human CYP450 isoforms involved in drug metabolism. The results showed strong inhibition of CYP1A2, CYP2E1 and CYP3A, with IC50 values up to 1.4 μM, and moderate inhibition of CYP2C19, with IC50 value >15 μM. Detailed experiments performed with human liver microsomes showed that the inhibition of CYP450 isoforms can be explained by competitive and non-competitive inhibition mechanisms. In addition, seriniquinone demonstrated to be an irreversible and time-dependent inhibitor of CYP1A2 and CYP3A. The low inhibition constants values obtained experimentally suggest that concomitant intake of seriniquinone with drug metabolized by these isoforms should be carefully monitored for adverse effects or therapeutic failure.
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Cytochrome P450, Human liver microsomes, in vitro metabolism, Inhibition mechanisms, Natural product-drug interaction, Seriniquinone
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Toxicology in Vitro, v. 65.