Bertrand Piver, Maude Fer, Xavier Vitrac, Jean-Michel Merillon, Yvonne Dreano, François Berthou, Danièle Lucas
Laboratory of Biochemistry, EA 948, Faculty of Medicine, CS 93837, 29238 Brest Cedex, France.
Biochemical pharmacology 2004 Aug 15This 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 microM, 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 alpha-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.
Bertrand Piver, Maude Fer, Xavier Vitrac, Jean-Michel Merillon, Yvonne Dreano, François Berthou, Danièle Lucas. Involvement of cytochrome P450 1A2 in the biotransformation of trans-resveratrol in human liver microsomes. Biochemical pharmacology. 2004 Aug 15;68(4):773-82
PMID: 15276085
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