Resveratrol modulates human mammary epithelial cell O-acetyltransferase, sulfotransferase, and kinase activation of the heterocyclic amine carcinogen N-hydroxy-PhIP.
Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural antioxidant found in plants, such as grapes, that studies suggest has cancer chemopreventive activity. We investigated the effects of resveratrol on DNA binding via esterification reactions with 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) - a metabolite of a mammary gland carcinogen present in cooked meats. Treatment of primary cultures of human mammary epithelial cells with 50 microM resveratrol led to a decrease in PhIP-DNA adducts ranging from 31 to 69%. Using substrate-specific assays and mammary gland tissue cytosols, resveratrol inhibited PhIP-DNA adduct formation by O-acetyltransferase and sulfotransferase catalysis. Cytosols from tumor tissue and breast reduction tissue were similarly affected. Resveratrol also suppressed O-acetyltransferase and sulfotransferase activities from the breast cancer cell lines MCF-7 and ZR-75-1. It was also observed that resveratrol stimulated ATP-dependent cytosolic activation of N-OH-PhIP in all human samples but not in mouse liver samples. In addition to resveratol's other preventive effects, the present data suggest that O-acetyltransferases and sulfotransferases may represent anti-oncogenic targets for resveratrol.
Dubuisson
Jeffrey G
JG
Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL 36688-0002, USA.
Dyess
Donna L
DL
Gaubatz
James W
JW
D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001711:Biotransformation; D001940:Breast / Q000187:drug effects / Q000201:enzymology*; D002273:Carcinogens / Q000493:pharmacokinetics*; D018736:DNA Adducts / Q000032:analysis; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000493:pharmacokinetics*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D011725:Pyridines; D013267:Stilbenes; C060533:2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D000123:Acetyltransferases; D010770:Phosphotransferases; D015238:Sulfotransferases; D000077185:Resveratrol