Role of dihydromyricetin in cytochrome P450-mediated metabolism and carcinogen activation.

OBJECTIVES: Dihydromyricetin (DHM) is a flavonoid, which has been shown to antagonize effects of ethanol intoxication. As a potential pharmacological agent, its biological interactions with enzymes metabolizing foreign compounds should be tested. Thus, the aim of this study was to analyze the influence of DHM on the induction and metabolic activity of selected cytochromes P450 (CYPs).

METHODS: After flavonoid administration by oral gavage to stomach the CYP expression at protein and mRNA levels was determined in rat liver and small intestine. The effects of flavonoids on CYP1A1/2, CYP1A2 or CYP2B1/2 enzyme activities in microsomes were measured using marker activities of these enzymes. Flavonoid-mediated inhibition of recombinant CYP1A2 was also assayed with luciferin-ME substrate. The flavonoid interaction with aryl hydrocarbon receptor (AhR) was assayed by reporter luciferase activity in Hep2G cells.

RESULTS: The value of half maximal inhibitory concentration of DHM for CYP1A1/2, CYP1A2, and CYP2B1 were determined to be 4.1, 14.2, and 98.5 mmol.L(-1), respectively. With the exception of a weak induction of CYP2B1 and CYP1A2 in the middle part of small intestine and in the liver, respectively, DHM did not affect the CYP expression at protein levels. On the contrary, real-time PCR revealed elevated expression of CYP1A1 and CYP1A2 mRNA in proximal part of the small intestine while decreased in the middle part. In the study utilizing the HepG2 cells, DHM showed only an additive effect on the benzo[a]pyrene-mediated activation of Ah receptor.

CONCLUSIONS: Dihydromyricetin doesn't significantly interfere with metabolic activity of CYP1A1/2 and CYP2B1 enzymes.

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