Inhibitory Potentials of Five Phytoestrogens from Pueraria candollei var. mirifica on CYP1A1 and CYP1A2 Proteins in Mouse Liver Microsomes and in silico

Abstract

Pueraria candollei var. mirifica (PM) is a Thai traditional medicinal plant for rejuvenation and estrogen replacement therapy in menopausal women. CYP1A1 and CYP1A2 proteins are the members of hepatic cytochrome P450 (CYP) enzymes to activate a procarcinogen, in which ethoxyresorufin O -deethylase (EROD) and methoxyresorufin O -demethylase (MROD) activities are the specific markers for CYP1A1 and CYP1A2, respectively. In the present study, the effects of five phytoestrogens isolated form the bark of PM tuberous roots namely miroestrol, deoxymiroestrol, khawkhurin, isomiroestrol, and methoxyisomiroestrol, on EROD and MROD activities were examined in mouse hepatic microsomes, compared to a typical CYP1A1/2 inducer and substrate beta-napthoflavone (BNF). The bindings of these five compounds to either CYP1A1 or CYP1A2 enzymes were analyzed using molecular docking with homology modeling technique. Rank of the median inhibitory concentration (IC 50 ) of these compounds on EROD activity corresponded to that of MROD, namely BNF > miroestrol > kwakhurin > deoxymiroestrol > methoxyisomiroestrol> isomiroestrol, respectively. Interestingly, the binding pose energy of these compounds to CYP1A1 and CYP1A2 proteins were consistent to those of inhibitory effects on EROD and MROD activities. The observations suggested for the first time that the active phytoestrogens from PM possessed inhibitory potentials on CYP1A1 and CYP1A2 via EROD and MROD activities, respectively. Furthermore, the binding energy of the compounds to CYP1A1 and CYP1A2 proteins might be a useful tool to predict the effects of a compound on these two CYP enzymes.