In Vitro mechanism-based inactivation of cytochrome P450 3A4 by a new constituent of Cinnamomum burmani

Abstract

Cytochrome P450 enzymes play an important role in drug metabolism. Various studies have reported the potential inhibition of these enzymes by natural compounds, leading to possible drug-herb interaction. One study reported that the MeOH extract of Cinnamomum burmani inhibited CYP3A4 in a mechanism-based mode. Further phytochemical investigation on this plant led to the isolation of 17 compounds including 2 new compounds: cinnamic aldehyde cyclic syringylglycerol 1,3-acetal (1) and 5'-hydroxy-5-hydroxymethyl-4'',5''-methylenedioxy-1,2,3,4-dibenzo-1,3,5-cycloheptatriene (2). The isolated constituents were tested for their preincubation time-dependent inhibition of CYP3A4 at 0 and 20 min. Only the new compound 2 showed an increase in the inhibitory activity to >50 % after 20-min preincubation. Further investigations of the inactivation by 2 displayed characteristics of a mechanism-based inactivator, with KI and kappainact values of 7.7 icroM and 0.04 min(-1), respectively.

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