Tuberculosis

Tuberculosis (TB) kills approximately two million people each year. It has been estimated that between 2002 and 2020, approximately 1000 million people will be newly infected, more than 150 million people will get sick, and 36 million will die of TB—if control is not further strengthened. Treatment requires combination therapy generally including iso-niazid, rifampin, ethambutol, and pyrazinamide for six to nine months. The success of therapy is greatly influenced by adherence, and by avoidance of toxicity, including the occurrence of fatal and severe liver injury associated with the combination of isonizid, rifampin, and pyrazinamide. Unfortunately, little is known about genetic predictors of tox-icity with the exception of the association between the acetylator polymorphism and the neurological toxicity of isoniazid.

Isoniazid continues to play an important role in the management of TB. The metabolism of isoniazid takes place in the liver by two metabolic pathways: phase I oxidative metabolism by the cytochrome P450 enzymes, and phase II N-acetylation mediated by NAT (51,52). N-acetylation is important in the biotransformation of drugs, such as isonia-zid, sulfonamides, and dapsone. The human acetylator polymorphism was one of the first hereditary traits affecting drug response to be discovered (5). This trait was found in patients who developed numbness and tingling in the fingers and toes after responding to isoniazid treatment (53). Further studies demonstrated that patients who were slow acet-ylators and excreted less acetyl-isoniazid were more prone to develop neurologic toxicity.

It is now known that the population ratio of rapid versus slow acetylators varies widely among different ethnic groups. The highest proportion of slow acetylators is found in Egyptians (80%), whereas 40% to 60% of the Caucasians and African Americans, and only 10% to 20% of the Japanese and Canadian Eskimos are slow acetylators. With some exceptions, the clinical consequences are that slow acetylators develop more adverse reactions, whereas rapid acetylators are more prone to have an inadequate response when prescribed a standard dose of the acetylated drug. Slow acetylators have been shown to be at risk of developing hypersensitivity reactions to drugs, such as sulfo-namides and dapsone, particularly in HIV-infected patients. In addition, recent studies have demonstrated that slow acetylators have a higher risk of isoniazid-induced hepato-toxicity than rapid acetylators (26.4% vs. 11.1%, respectively) (10). In slow acetylators, the amount of NAT found in the liver is reduced, and in rapid acetylators the level of NAT activity present is at least twice as high as that found in slow acetylators (54,55).

Earlier studies suggested that acetylation capacity was a heritable autosomal trait, where the slow acetylators carried the homozygous gene for slow acetylation and the rapid acetylators carried either the homozygous or heterozygous gene for rapid acety-lation. In man, three NAT genes have been found, with only the NAT1 and NAT2 genes being expressed (56). NAT1 shows kinetic selectivity for monomorphic substrates, such as p-aminobenzoic acid and p-aminosalicylic acid, whereas NAT2 is more important for clinically relevant substrates, such as isoniazid and sulfamethazine.

The NAT2 acetylation polymorphism is one of the most common polymorphisms known in human populations (57,58). The reference NAT2*4 is associated with the rapid acetylator phenotype and at least 25 NAT2 allelic variants have been identified that account for 95% or more of the alleles in Caucasians, Asians, Hispanics, and African Americans (59,60). These alleles contain 11 different single-nucleotide polymorphisms (SNPs) in the NAT2 coding region. A recent study investigated the functional effects of each of the 11 SNPs on NAT2 catalytic activity, protein expression, and stability (60). In this study, a reduction in catalytic activity for the N-acetylation of sulfamethazine was observed for NAT2 variants possessing G191A (R64Q), T341C (I114T), A434C (E145P), G590A (R197Q), A845C (K282T), or G857A (G286T). A reduction in expression of NAT2 immunoreactive protein was also observed for NAT2 variants possessing T341C, A434C, or G590A. A reduction in protein stability was noted for NAT2 variants possessing G191A, A845C, G857A, and G590A. No significant differences in mRNA expression or transformation efficiency were observed among any of the NAT2 alleles. The investigators concluded that variations in stability and catalytic activity were the mechanisms responsible for the slow acetylator phenotype. In patients who are at high risk of developing adverse effects or inadequate response to therapy, assessing the acetylator status might be useful in tailoring drug therapy to ensure maximal response.

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