In Vitro and In Vivo Effects of Resveratrol on Rat Hepatic CYP1A2

<b>Background/Objectives:</b> Although several studies have been reported on the modulation of Cytochrome P450 by resveratrol, inconsistencies in the results obtained require further investigation. Here, we report the results of in vivo and in vitro experiments investigating the effect of resveratrol on CYP1A2, which participates in the biotransformation of several drugs used for the treatment of human malignancies. <b>Methods:</b> Male Wistar rats were exposed to resveratrol through diet (1%) for 30 days, and the hepatic CYP1A2 activity and protein concentration were assayed at the end of the treatment. Additionally, the capacity of the phytochemical to interfere with the induction of CYP1A2 by benzo[a]pyrene (50 mg/kg body weight) was also studied. The inhibition of CYP1A2 activity in rat liver microsomal and recombinant human enzymes by resveratrol, as well as its inhibitory kinetics and type of inhibition, were compared. <b>Results:</b> No significant increase in the protein concentration of hepatic CYP1A2 was found in resveratrol-treated rats, but it induces CYP1A2 activity and enhances the induction effect of benzo[a]pyrene. In silico and in vitro experiments demonstrated that resveratrol binds to the active site of human CYP1A2 through hydrophobic interactions with PHE125, PHE226, PHE260, and ALA317, and hydrogen bonds with SER122 and ASP313. It inhibits human recombinant CYP1A2 activity as well as that in rat liver microsomes, with IC₅₀ values of 46 µM and 485 µM, respectively. Resveratrol showed a mixed type of inhibition of recombinant human protein and a competitive inhibition of rat liver microsomal CYP1A. <b>Conclusions:</b> We can conclude that resveratrol is an in vitro inhibitor of CYP1A2, but it increases the benzo[a]pyrene CYP induction effect in vivo.