Pharmacogenetics and Cardiac Ion Channels

Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Nashville, Tennessee, U.S.A. 

The anticoagulant warfarin is increasingly used to prevent thromboembolic complications in patients with atrial fibrillation. The drug is administered as racemate, and bio-inactivation of the active S-enantiomer is accomplished by CYP2C9. Relatively common variants in CYP2C9 that reduce its function have been described, and homozygotes for reduction of function alleles 

Importantly, these clinical studies were executed at a time when the molecular basis of the slow and fast acetylator phenotypes were not well understood. We now know that there are two isoforms of the /V-acetyltrans-ferase enzyme arising from two different genes, NAT1 and NAT2. Constitutive expression of NAT1 accounts for basal enzyme function, and functionally important polymorphisms in NAT2, are thought to contribute to variability in overall enzymatic activity and thus to define the slow- and fast-acetylators phenotypes (23,24). 

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Anantharam, A., Markowitz, S.M. and Abbott, G.W. (2003) Pharmacogenetic considerations in diseases of cardiac ion channels. The Journal of Pharmacology and Experimental Therapeutics, 307, 831-838. 

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