Involvement of cytochrome P450 1A2 in the biotransformation of trans-resveratrol in human liver microsomes.
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 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.
Piver
Bertrand
B
Laboratory of Biochemistry, EA 948, Faculty of Medicine, CS 93837, 29238 Brest Cedex, France.
Fer
Maude
M
Vitrac
Xavier
X
Merillon
Jean-Michel
JM
Dreano
Yvonne
Y
Berthou
François
F
Lucas
Danièle
D
D000975:Antioxidants / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001711:Biotransformation; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism*
D000975:Antioxidants; D011994:Recombinant Proteins; D013267:Stilbenes; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D000077185:Resveratrol