Minder E I, Meier P J, Müller H K, Minder C, Meyer U A
Eur J Clin Invest. 1984 Jun;14(3):184-9. doi: 10.1111/j.1365-2362.1984.tb01121.x.
The genetically controlled polymorphism causing decreased metabolism of debrisoquine is closely related to that of the metabolism of bufuralol and numerous other drugs and has important clinical consequences. A sensitive in vitro assay was developed which quantifies the production of 1'-hydroxy-bufuralol (carbinol) from bufuralol in human liver microsomes. Initial formation rates of carbinol suggested Michaelis-Menten kinetics with an apparent KM of 61 and 171 mumol l-1 and Vmax of 3.2 and 5.8 nmol mg-1 microsomal protein h-1 in two human liver samples. The Vmax in microsomes of thirty-two liver samples was 4.2 +/- 1.0 (SD) nmol carbinol mg-1 protein h-1. Metabolism of debrisoquine in vivo, as expressed by the 'metabolic ratio' of debrisoquine over 4-OH debrisoquine correlated (r = -0.65, P less than 0.01; n = 18) with carbinol production rate in microsomes in vitro. Microsomes of one individual identified as poor metabolizer of debrisoquine in vivo showed reduction of carbinol formation to 1.97 nmol mg-1 h-1. Mixing his microsomes with those of an extensive metabolizer resulted in additive formation of carbinol excluding mediation of the defect by a soluble inhibitor. These data support the concept of a primary defect in microsomal oxidation of bufuralol. The described assay offers a sensitive tool to investigate the molecular mechanism of the 'debrisoquine polymorphism'.
