Variable contribution of CYP2D6 to the N-dealkylation of S-(-)-propranolol by human liver microsomes

Recombinant cDNA expression systems for CYP2D6 have been shown to have significant catalytic activity with respect to the N-dealkylation of propranolol. However, the involvement of CYP2D6 in this reaction in human liver is inconclusive. We have re-evaluated the role of CYP2D6 in the dealkylation of S-(-)-propranolol using a bank of 10 human livers characterized for their specific CYP2D6 and CYP1A2 activities, the latter enzyme being known to be involved substantially in the formation of N-desisopropylpropranolol. Using quinidine (1 microM) or LKM-1 antibodies as selective inhibitors of CYP2D6, the contribution of this enzyme to net N-desisopropylation of S-(-)-propranolol (10 microM) by microsomes from the range of livers was found to vary from nil (poor metabolizer genotype) to 60%. N-desisopropylpropranolol formation inhibitable by quinidine was highly correlated with specific CYP2D6 activity, as measured by the alpha-hydroxylation of metoprolol (rs = 0.90; P < 0.001). The two livers with the highest proportion of CYP2D6-mediated N-dealkylation had relatively high ratios of specific CYP2D6 to CYP1A2 activity. These findings emphasize that data obtained using microsomes from single human livers or pooled microsomes from several livers may be misleading inasmuch as the relative contribution of different isoenzymes to the same metabolic reaction may show considerable between-subject variation.