In Vitro Inhibition of Human CYP450s 1A2, 2C9, 3A4/5, 2D6 and 2E1 by Grandisin

Author(s)

Habenschus, Maisa Daniela ; Moreira, Fernanda de Lima ; Lopes, Norberto Peporine ; de Oliveira, Anderson R. M.

• Document type: Journal article
• Source: Planta Medica; v. 83, n. 8, p. 727-736, MAY 2017.
• Web of Science Citations: 4

Abstract

Grandisin, a lignan isolated from many species of plants, such as Virola surinamensis, is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of gran dish on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent K-i value for CYP2C9 was 50.60 mu M and those for CYP3A4/5 were 48.71 mu M and 31.25 mu M using two different probe substrates, nifedipine and midazolam, respectively. The apparent K-l, k(inact), and k(inact)/K-l ratio for the mechanism-based inhibition of CYP3A4/5 were 6.40 mu M, 0.037 min-1, and 5.78 mL.min(-1) mu mol(-1) respectively, by examining nifedipine oxidation, and 31.53 mu M, 0.049 min(-1), and 1.55 mL.min(-1) mu mol(-1), respectively, by examining midazolam 1'-hydroxylation. These apparent k(inact)/K-I values were comparable to or even higher than those for several therapeutic drugs that act as mechanism-based inhibitors of CYP3A4/5. CYP1A2 and CYP2D6 activities, in turn, were not substantially inhibited by grandisin (IC50 >200 mu M and 100 mu M, respectively). In contrast, from a concentration of 4 pM, grandisin significantly stimulated CYP2E1 activity. These results improve the prediction of grandisin-drug interactions, suggesting that the risk of interactions with drugs metabolized by CYP3A4/5 and CYP2E1 cannot be overlooked. (AU)

• FAPESP's process: 13/17658-9 - Development and validation of chromatographic and electrophoretic methods for subsequent application in studies of in vitro metabolism and biotransformation - phase 2
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/07597-0 - Development of chromatographic/electrophoretic methods to be further used in in vitro enzymatic inhibition and drug interaction of chiral pesticides
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support Opportunities: Regular Research Grants
• 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