We examined the oxidative metabolism of a K-blocker bunitrolol (BTL) by 10 human cytochromes P450 (CYP) (1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A3, 3A4 or 3A5), which were individually expressed in Hep G2 cells with a vaccinia virus complementary DNA expression system. Among the 10 isozymes, only CYP2D6 and 1A2 at a substrate concentration of 5 μm, and CYP2C8 and 2C9 in addition to the two isozymes at a BTL concentration of 1 mM, exhibited detectable BTL 4-hydroxylase activities. The activities at 1 mM BTL were on the order of CYP2D6 (100% as relative activity)>CYP1A2 (86%) » CYP2C8 and 2C9 (7-8%). Enzyme kinetic parameters of CYP2D6 were calculated to be 4.41μm as a Km value and 0.442 nmol min-1 per nmol CYP as a Vmax value. Kinetic parameters of CYP1A2 were calculated as 295 μm and 0.411 nmol min-1 per nmol CYP for Km and Vm values, respectively. These results suggest that both CYP2D6 and 1A2 primarily catalyse BTL 4-hydroxyIation, but that the former is a predominant isozyme responsible for the reaction at a low substrate concentration range of BTL in human liver.
- Human cytochromes P450
- Oxidative metabolism
- Vaccinia virus
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)