Autor(es): 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]
Data: 2020
Identificador Persistente: http://hdl.handle.net/11449/201112
Origem: Oasisbr
Assunto(s): Cytochrome P450; Human liver microsomes; in vitro metabolism; Inhibition mechanisms; Natural product-drug interaction; Seriniquinone
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
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.
Núcleo de Pesquisas de Produtos Naturais e Sintéticos Departamento de Ciências BioMoleculares Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo
Departamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo
Departamento de Ciências do Mar Instituto do Mar Universidade Federal de São Paulo
CMBB Scripps Institution of Oceanography UC San Diego, 9500 Gilman Drive No. 0204
Departamento de Farmacologia Instituto de Ciências Biomédicas Universidade de São Paulo
National Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT–DATREM) Unesp Institute of Chemistry, P.O. Box 355
National Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT–DATREM) Unesp Institute of Chemistry, P.O. Box 355
FAPESP: 2014/50265-3
FAPESP: 2014/50945-4
FAPESP: 2015/17177-6
FAPESP: 2016/06366-5
FAPESP: 2016/15680-5
FAPESP: 2018/07534-4
CNPq: 465571/2014-0
