Involvement of the CYP1A subfamily in stereoselective metabolism of carvedilol in beta-naphthoflavone-treated Caco-2 cells.

We have previously reported that the metabolism of S-carvedilol in beta-naphthoflavone (beta-NF)-treated Caco-2 cells is faster than that of R-carvedilol. The aim of the present study was to identify the enzyme responsible for the stereoselective metabolism of carvedilol in the cells. The expression of cytochrome P450 (CYP) 1A1 and CYP1A2 mRNA, but not CYP2D6, CYP3A4, and CYP2C9 mRNA, was increased in beta-NF-treated Caco-2 cells, as compared with non-treated cells. Furafylline, an inhibitor of the CYP1A subfamily, decreased the metabolism of S-carvedilol in Caco-2 cells cultured on plastic dishes. In addition, the glucuronidation of carvedilol was not significant in microsomes of beta-NF-treated Caco-2 cells. On the other hand, the oxidation of S-carvedilol in microsomes of beta-NF-treated Caco-2 cells was faster than that of R-carvedilol, and furafylline decreased the oxidative activity of S-carvedilol. These findings suggested that the CYP1A subfamily was responsible for the stereoselective metabolism of carvedilol in beta-NF-treated Caco-2 cells.