Submitted to: Xenobiotica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/25/2005
Publication Date: 4/4/2006
Citation: Mikstacka, R., Rimando, A.M., Szalaty, K., Stasik, K., Baer-Dubowska, W. 2006. Effect of natural analogues of trans-resveratrol on cytochrome p450 1A2 and 2E1 catalytic activities. Xenobiotica. 36(4):269-285. Interpretive Summary: Resveratrol and several closely related compounds have been reported as cancer chemopreventive agents. One of the most important strategies for cancer chemoprevention is the inhibition of cytochrome P450 type enzymes. The inhibitory activity of these compounds against two of these enzymes was investigated. Certain compounds related to resveratrol were found to be potent inhibitors of one of these P450 enzymes, with pterostilbene, a constituent of blueberries, being the most potent. This study provided valuable information on the chemical structure attributes needed for good inhibition of P450 enzymes associated with cancer. Inhibition of these enzymes by these naturally-occurring compounds may be important for their cancer chemopreventive activity.
Technical Abstract: The effects of a series of naturally occurring trans-resveratrol analogues on 7-ethoxyresorufin O-deethylase (EROD) and p-nitrophenol hydroxylase (PNPH) was evaluated in mouse liver microsomes in vitro. The relationship between structure and potential inhibitory effect on cytochrome P450 dependent enzymes was analysed. 3,4',5-Trimethoxy-trans-stilbene (TMS), 3,5-dimethoxy-4'-hydroxy-trans-stilbene (pterostilbene) and monomethylether trans-resveratrol derivatives, 3,4'-dihydroxy-5-methoxy-trans-stilbene (3,4'-DH-5-MS) and 3,5-dihydroxy-4'-methoxy-trans-stilbene (3,5-DH-4'-MS) inhibited the activity of EROD in a concentration-dependent manner, with Ki values 0.79, 0.39, 0.94 and 1.04 uM, respectively. Pterostilbene and the monomethylether analogues of trans-resveratrol inhibited EROD activity in a mixed (competitive/noncompetitive) manner while TMS appeared to be a competitive inhibitor of this CYP1A2 enzymatic marker. The studies on human recombinant CYP 1A2 confirmed the data with regard to 3,5-DH-4'-MS and 3,4'-DH-5-MS. Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene) was the least potent inhibitor of CYP1A2 with Ki value equal to 9.67 uM. In contrast to resveratrol, piceatannol, pterostilbene and TMS in the concentration range from 5 to 100 uM did not inhibit the activity of PNPH. The activity of this enzyme was likewise not significantly influenced by 3,5-DH-4'-MS in the concentration range up to 0.2 mM, whereas 3,4'-DH-5-MS appeared to be a moderately potent inhibitor of PNPH (IC50 = 72 uM; Ki = 42.6 uM), and a competitive type of inhibition was demonstrated. The structure-activity relationship analysis leads to the conclusion that the number and position of methylation of the hydroxyl groups in resveratrol are not as critical as the substitution of the hydroxy with a methoxy group for the increased inhibition of CYP1A2. In contrast, the 4'-hydroxy group in trans-resveratrol and its analogues may play an important role in the interaction with a binding site and the specific inhibition of CYP 2E1, the isozyme responsible for the activation of ubiquitous chemical carcinogens. Since both CYP1A2 and CYP2E1 are responsible for the bioactivation of several procarcinogens their inhibition by naturally occurring monomethylether analogues of resveratrol may be important for potential chemopreventive activity of these compounds.