In Vitro Metabolism of Artepillin C by Rat and Human Liver Microsomes

Artepillin C, a natural product present in the Brazilian green propolis, has several biological properties. Among these properties, the antitumor action of this product is noteworthy and makes it a promising drug candidate for the treatment of several types of cancer. This paper describes the in vitro metabolism of Artcpillin C in rat and human liver microsomcs. Thc rat model suggested a sigrnoidal profile for the metabolism, adapted to the Hill's kinetic model. The enzymatic kinetic parameters were as follows: maximal velocity = 0.757 +/- 0.021 mu mol/mg protein/min, Hill coefficient= 10.90 +/- 2.80, and substrate concentration at which half-maximal velocity of a Hill enzyme is achieved =33.35 +/- 0.55 mu M. Based on these results, the calculated in vitro intrinsic clearance for Artepillin C was 16.63 +/- 1.52 mu L/min/mg protein. The in vitro metabolism assay conducted on the human model did not fit any enzymatic kinetic model. Two novel metabolites were formed in both mammal microsomal models and their chemical structures were elucidated for the first time. The main human cytochromc P450 isoforms involved in Artcpillin C metabolism had been identified, and the results suggest a majority contribution of CYP2E1 and CYP2C9 in the formation of the two metabolites.