Effect of natural analogues of trans-resveratrol on cytochromes P4501A2 and 2E1 catalytic activities

• Published in: Xenobiotica Vol. 36; no. 4; pp. 269 - 285
• Main Authors: Mikstacka, R., Rimando, A. M., Szalaty, K., Stasik, K., Baer-Dubowska, W.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.04.2006; Taylor & Francis
• Subjects: Animals; Catalytic Domain; Chemoprevention; CYP1A2; CYP2E1; Cytochrome P-450 CYP1A2 - chemistry; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2E1 - chemistry; Cytochrome P-450 CYP2E1 - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Female; Inhibitory Concentration 50; Kinetics; Liver - drug effects; Liver - enzymology; Mice; Resveratrol; stilbene derivatives; Stilbenes - chemistry; Stilbenes - pharmacology; trans-resveratrol
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498250500485057

The aim was to assess the inhibitory effect of a series of naturally occurring trans-resveratrol analogues on cytochromes P450, namely CYP1A2 and CYP2E1, in vitro in order to analyse any structure-activity relationships. 3,5-Dimethoxy-4′-hydroxy-trans-stilbene (pterostilbene), 3,4′,5-trimethoxy-trans-stilbene (TMS), 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 CYP1A2, with Ki = 0.39, 0.79, 0.94 and 1.04 µM, respectively. Piceatannol (3,3′,4,5′-tetrahydroxy-trans-stilbene) was the least potent inhibitor of CYP1A2 with a Ki = 9.67 µM. Piceatannol and TMS in the concentration range 1-100 µM did not inhibit CYP2E1 activity. The activity of this enzyme likewise was not significantly influenced by pterostilbene and 3,5-DH-4′-MS with IC50 > 100 µM, whereas 3,4′-DH-5-MS appeared to be a moderately potent, competitive inhibitor of CYP2E1 (Ki = 42.6 µM). Structure-activity relationship analysis leads to the conclusion that the substitution of hydroxy groups of resveratrol with methoxy groups increases the inhibition of CYP1A2, yet the number and position of methylation are not essential. However, the 4′-hydroxy group in trans-resveratrol and its analogues may play an important role in the interaction with a binding site of CYP2E1.