Ishida Kazuya, Taguchi Masato, Akao Teruaki, Hashimoto Yukiya
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
Biol Pharm Bull. 2009 Mar;32(3):513-6. doi: 10.1248/bpb.32.513.
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.
我们之前曾报道，在经β-萘黄酮（β-NF）处理的Caco-2细胞中，S-卡维地洛的代谢比R-卡维地洛更快。本研究的目的是确定负责细胞中卡维地洛立体选择性代谢的酶。与未处理的细胞相比，经β-NF处理的Caco-2细胞中细胞色素P450（CYP）1A1和CYP1A2 mRNA的表达增加，但CYP2D6、CYP3A4和CYP2C9 mRNA的表达未增加。CYP1A亚家族的抑制剂呋拉茶碱降低了在塑料培养皿上培养的Caco-2细胞中S-卡维地洛的代谢。此外，在经β-NF处理的Caco-2细胞的微粒体中，卡维地洛的葡萄糖醛酸化并不显著。另一方面，在经β-NF处理的Caco-2细胞的微粒体中，S-卡维地洛的氧化比R-卡维地洛更快，且呋拉茶碱降低了S-卡维地洛的氧化活性。这些发现表明，CYP1A亚家族负责经β-NF处理的Caco-2细胞中卡维地洛的立体选择性代谢。
