Involvement of cytochrome P450 1A2 in the biotransformation of trans-resveratrol in human liver microsomes

Abstract

This study was aimed at identifying the isoform(s) of human liver cytochrome P450 (CYP) involved in the hepatic biotransformation of trans-resveratrol ( trans-3,5,4′-trihydroxystilbene). Trans-resveratrol metabolism was found to yield two major metabolites, piceatannol (3,5,3′,4′-tetrahydroxystilbene) and another tetrahydroxystilbene named M1. Trans-resveratrol was hydroxylated to give piceatannol and M1 with apparent K m of 21 and 31 μM, respectively. Metabolic rates were in the range 14–101 pmol min −1 mg −1 protein for piceatannol and 29–161 pmol min −1 mg −1 protein for M1 in the 13 human liver microsomes tested. Using microsomal preparations from different human liver samples, piceatannol and M1 formation significantly correlated with ethoxy-resorufin- O-deethylation ( r 2 = 0.84 and 0.88, respectively), phenacetin- O-deethylation ( r 2 = 0.92 and 0.94) and immuno-quantified CYP1A2 ( r 2 = 0.85 and 0.90). Formation of these metabolites was markedly inhibited by α-naphthoflavone and furafylline, two inhibitors of CYP1A2. Antibodies raised against CYP1A2 also inhibited the biotransformation of trans-resveratrol. In addition, the metabolism of trans-resveratrol into these two metabolites was catalyzed by recombinant human CYP1A1, CYP1A2 and CYP1B1. Our results provide evidence that in human liver, CYP1A2 plays a major role in the metabolism of trans-resveratrol into piceatannol and tetrahydroxystilbene M1.