Prediction of seriniquinone-drug interactions by in vitro inhibition of human cytochrome P450 enzymes

Author(s)

da Silva, Rodrigo Moreira ^[1] ; Carrao, Daniel Blascke ^[2] ; Habenschus, Maisa Daniela ^[2] ; Jimenez, Paula Christine ^[3] ; Lops, Norberto Peporine ^[1] ; Fenical, William ^[4] ; Costa-Lotufo, Leticia Vera ^[5] ; Moraes de Oliveira, Anderson Rodrigo ^{[2, 6]}

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias Biomol, Nucleo Pesquisas Produtos Nat & Sintet, Av Cafe S-N, BR-14090903 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Dept Quim, Fac Filosofia Ciencias & Letras Ribeirao Preto, BR-14040901 Ribeirao Preto, SP - Brazil

^[3] Univ Fed Sao Paulo, Inst Mar, Dept Ciencias Mar, BR-11070100 Santos, SP - Brazil

^[4] Univ Calif San Diego, Scripps Inst Oceanog, CMBB, 9500 Gilman Dr 0204, La Jolla, CA 92093 - USA

^[5] Univ Sao Paulo, Inst Ciencias Biomed, Dept Farmacol, BR-05508900 Sao Paulo, SP - Brazil

^[6] UNESP, Inst Chem, Natl Inst Alternat Technol Detect Toxicol Evaluat, INCT DATREM, POB 355, BR-14800900 Araraquara, SP - Brazil

• Document type: Journal article
• Source: TOXICOLOGY IN VITRO; v. 65, JUN 2020.
• Web of Science Citations: 0

Abstract

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 mu M, and moderate inhibition of CYP2C19, with IC50 value > 15 mu M. 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. (AU)

• FAPESP's process: 14/50265-3 - Distribution and metabolism of natural and synthetic xenobiotics: from the comprehension of reactional process to tissue imaging generation
• Grantee: Norberto Peporine Lopes
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 14/50945-4 - INCT 2014: National Institute for Alternative Technologies of Detection, Toxicological Evaluation and Removal of Micropollutants and Radioactivies
• Grantee: Maria Valnice Boldrin
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/15680-5 - Enantioselective in vitro studies of metabolism, enzymatic inhibition and toxicity of the pesticide fipronil
• Grantee: Daniel Blascke Carrão
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/06366-5 - Natural and synthetic xenobiotics bioavailability on in vitro models
• Grantee: Rodrigo Moreira da Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/07534-4 - Development of chromatographic / electrophoretic methods to be further applied in in vitro enzymatic inhibition studies and prediction of drug interactions of chiral pesticides - Phase 2
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support Opportunities: Regular Research Grants