Genetic Basis of Drug Metabolism

Margaret K. Ma, Michael H. Woo, Howard L. Mcleod

Disclosures

Am J Health Syst Pharm. 2002;59(21) 

In This Article

N-Acetyltransferase

The acetylation polymorphism illustrates another genetic polymorphism of a drug-metabolizing enzyme studied in the early era of pharmacogenetics. N-acetyltransferase (gene, NAT), a phase-II conjugating liver enzyme, catalyzes the N-acetylation (usually deactivation) and O-acetylation (usually activation) of arylamine carcinogens and heterocyclic amines. The slow acetylator phenotype often experiences toxicity from drugs such as isoniazid, sulfonamides, procainamide, and hydralazine, whereas the fast acetylator phenotype may not respond to isoniazid and hydralazine in the management of tuberculosis and hypertension, respectively. During the development of isoniazid, isoniazid plasma concentrations were observed in a distinct bimodal population after a standard dose. Patients with the highest plasma isoniazid levels were generally slow acetylators and they suffered from peripheral nerve damage, while fast acetylators were not affected.[15] Slow acetylators are also at risk for sulfonamide-induced toxicity and can suffer from idiopathic lupus erythematosus while taking procainamide.[16,17,18] The slow acetylator phenotype is an autosomal recessive trait. Studies have shown large variations of the slow acetylator phenotype among ethnic groups: 40- 70% of Caucasians and African-Americans, 10-20% of Japanese and Canadian Eskimo, more than 80% of Egyptians, and certain Jewish populations are slow acetylators.[19,20] In East Asia, the further north the geographic origin of the population, the lower the frequency of the slow acetylator gene.[21,22,23] The reason for this trend is unknown, but it has been speculated that differences in dietary habits or the chemical or physical environment may be contributing factors.

Allelic variation at the NAT2 gene locus accounts for the polymorphism seen with acetylation of substrate drugs. There are 27 NAT2 alleles that have been reported. NAT2 is an unusual gene because it consists of open-reading frames (i.e., protein-coding regions) with no introns. Most variant NAT2 alleles involve two or three point mutations. For example, the variant NAT2*5B differs from the wild-type at three nucleotide positions, 341, 481, and 803; NAT2*6A has two changes at positions 282 and 590; NAT*13 has one point mutation at 282; and NAT2*7A has two changes at positions 282 and 857.[18]NAT2*5B and *6A account for 72-75% of all the variant NAT2 alleles, which includes at least 94% of all variant alleles in Caucasians, Japanese, and Hispanics and 83% of the NAT2 alleles in African-Americans. NAT2*5B is the most common allele in Caucasians (40-46%), but occurs at a very low frequency in Japanese (0.5%).[24,25,26]NAT*6A, *7B, and *13 share a mutation at C282T. NAT*5A,*5B, *6A, *7A, *7B, and *13 are associated with the slow acetylator phenotype as a result of a decrease in the amount of NAT2 protein. The protein expressed from NAT2*5A, *5B, and *5C genes has lower activities than *6A and *7B, whereas *13 has normal activity.[27]

Currently, the importance of these variants in NAT2 is most studied for their association with a modestly increased risk for cancers, possibly because of prolonged exposure of the body to chemicals, drugs, or metabolites compared with fast acetylators.[28] A recent preliminary result suggested that impaired isoniazid metabolism is associated with point mutations in NAT2 in a small Japanese population.[29] This exciting result awaits large population studies to establish clearly the relationship between the NAT2 genotype and isoniazid acetylation. It still takes some time to establish the clinical utility of NAT2 genotype analysis to independently predict isoniazid acetylation. However, genotype NAT2 mutations could be an addition to the traditional therapeutic drug monitoring for isoniazid in the near future.

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