Numerous studies have shown ethnic or racial differences in the pharmacokinetics of drugs; these kinetic differences are most commonly due to differences in hepatic metabolism. Two previous studies have shown that concentrations of the B-adrenergic receptor blocker, propranolol are significantly lower in African Americans than Caucasians. Clinical studies have documented that propranolol is significantly less effective as an antihypertensive agent in African Americans than in Caucasians, and the difference in propranolol kinetics may contribute to the racial differences in its antihypertensive efficacy. The primary aim of the current study is to identify and characterize the enzyme responsible for the racial differences in propranolol kinetics. Data from a previous study suggest the racial differences in propranolol kinetics are most likely due to differences in propranolol 4-hydroxylation. At least two high affinity cytochrome P450 (CYP) enzymes are responsible for propranolol 4-hydroxylation: CYP2D6 and another unidentified CYP. Studies using a prototypical CYP2D6 substrate, metoprolol, suggest there are no racial differences in metabolism via CYP2D6. Thus, the hypothesis for the current study is that the other enzyme which 4-hydroxylates propranolol exhibits racial differences in its catalytic activity.
The first aim of this study is to identify and characterize this putative enzyme. This will be done by screening for propranolol hydroxylase activity in recombinant human CYPs, followed by inhibition and correlation studies in human liver microsomes (HLMs). The second study aim is to characterize racial differences in propranolol hydroxylase activity in HLMs from 20 African Americans and 20 Caucasians. Although African Americans are the largest single minority group in this country, relatively little is known about differences between them and Caucasians in drug metabolism by the cytochrome P450 enzymes. The major purpose of this study is to identify a CYP which may have important differences in catalytic activity between African Americans and Caucasians. Identification of hepatic enzymes whose activities differ between ethnic groups is important since hepatic metabolism is responsible for activating or inactivating many xenobiotics (e.g. drugs and carcinogens). Differences between ethnic groups in hepatic metabolism may place one ethnic group at increased risk of therapeutic failure or toxicity, or increased cancer risk. Identification of enzymes which differ in activity between African Americans and Caucasians is important as it will allow for development of strategies to prevent or minimize these risks.
|Johnson, J A; Herring, V L; Wolfe, M S et al. (2000) CYP1A2 and CYP2D6 4-hydroxylate propranolol and both reactions exhibit racial differences. J Pharmacol Exp Ther 294:1099-105|
|Johnson, J A; Akers, W S; Herring, V L et al. (2000) Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs. Pharmacotherapy 20:622-8|