1994 Volume 9 Issue supplement Pages 168-171
Propranolol was converted by rat liver microsomes (Ms) into primary metabolites including 4-hydroxypropranolol (4-OH-PL). Preincubation of 4-OH-PL with Ms and NADPH caused inhibition of the ring hydroxylase activities of PL catalyzed by the CYP2D subfamily. 4-OH-PL eliminated quickly during incubation with Ms and NADPH. The 4-OH-PL elimination was changed not by inhibitors of CYP and FAD-monooxygenase or hydroxyl radical scavengers, but by ascorbic acid (1 mM). The microsomal 4-OH-PL elimination was markedly suppressed by cytosol, and the suppressive effect was blocked by KCN (5 mM). Purified Cu, Zn-SOD well mimicked the cytosolic effect, indicating that superoxide is resposible for microsomal 4-OH-PL elimination. 1, 4-Naphthoquinone (1, 4-NQ) was identified as a metabolite of 4-OH-PL in xanthine-xanthine oxidase and microsomal systems. Binding study using 3-3H-4-OH-PL and 4-OH-PL having 14C at the naphthalene ring showed that during incubation with Ms and NADPH, 3-5% of 3H and 20% of 14C-labeled substrates consumed covalently bound to microsomal protein. These results suggest that 4-OH-PL is converted into 1, 4-NQ by superoxide derived from CYP or fp2, and the quinone metabolite binds to microsomal protein including CYP isozymes, indicating a possible mechanism in the inactivation of CYP2D subfamily.
