Alteration of xenobiotic metabolizing enzymes by resveratrol in liver and lung of CD1 mice.
Conflicting data on the anticancer properties of the polyphenolic natural product resveratrol (RSV) have been reported. Since the inhibition of "bioactivating" Phase-I xenobiotic metabolizing enzymes (XMEs) and/or induction of "detoxifying" Phase-II XMEs have long been considered important cancer chemopreventive strategies, in the current study we investigated the effect of RSV treatment on several Cytochrome P450 (CYP)-dependent oxidations and Phase-II markers in liver and lung subcellular preparations from CD1 male mice. These mice were i.p treated with RSV (25 or 50mg/Kg b.w.) daily for one or for seven consecutive days. Using either specific probes for different CYPs, or the regio- and stereo-selective metabolism of testosterone, we found that most of the Phase-I XMEs were significantly suppressed (up to approximately 61% loss for the CYP3A1/2-linked 6 beta-hydroxylation of testosterone in liver and up to approximately 97% loss for 2 alpha-hydroxylase in lung) following RSV treatment for 7 days at 50mg/kg b.w. Glutathione S-transferase was significantly inhibited, particularly in lung (approximately 76% loss of activity) after single administration of 25mg/kg b.w. A different response for the UDP-glucuronosyl transferase was observed, where a significant induction was seen (approximately 83%) in the liver and a significant reduction was observed in the lung (up to approximately 83% loss) following treatment with 25mg/kg b.w. for seven days. These data indicate that murine XMEs are altered by RSV, and that this alteration is dependent on the RSV dose, duration and way of administration. These results could provide mechanistic explanations for the conflicting chemopreventive results reported for RSV.
Canistro
D
D
Department of Pharmacology, Molecular Toxicology Unit, Alma Mater Studiorum-University of Bologna, Via Irnerio 48, 40126 Bologna, Italy. labpaolini.farmacologia@unibo.it
Bonamassa
B
B
Pozzetti
L
L
Sapone
A
A
Abdel-Rahman
S Z
SZ
Biagi
G L
GL
Paolini
M
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D008815:Mice, Inbred Strains; D010088:Oxidoreductases / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014166:Transferases / Q000378:metabolism*
D016588:Anticarcinogenic Agents; D013267:Stilbenes; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D014166:Transferases; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D000077185:Resveratrol