Isoniazid polymorphism

Both these substituted hydrazine drugs may cause liver damage after therapeutic doses. With isoniazid, a mild hepatic dysfunction may occur in 10% to 20% of patients and a more severe type in less than 1%. Both isoniazid and iproniazid yield hydrazine metabolites (acetylhy-drazine and isopropylhydrazine, respectively), which are responsible for the hepatotoxicity after activation by cytochrome P-450. Isoniazid undergoes acetylation, which in humans is polymorphic. Slow acetylators are more at risk from the hepatotoxicity because acetylhy-drazine is detoxified by acetylation. 

Genetic polymorphism in drug metabolism. The graph shows the distribution of plasma concentrations of isoniazid in 267 individuals 6 hours after an oral dose of 9.8 mg/kg. This distribution is clearly bimodal. Individuals with a plasma concentration greater than 2.5 mg/mL at 6 hours are considered slow acetylators. (Redrawn, with permission, from Evans DAP, Manley KA, McKusick VA Genetic control of isoniazid metabolism in man. Br Med J 1960 2 485.)... 

Commonly used drugs (other than isoniazid) affected by NAT2 polymorphism were procainamide, hydralazine, dapsone, and sulfonamides with an increase of side effects in all cases. A selective substrate of NATl is -aminosalicylic acid (PAS), but its genetic variation was never clinically important (52). Because of such lack of importance, more attention is often paid to the fact that various industrial chemicals with carcinogenic potential, and mutagenic heterocyclic amines, are substrates of both N-acetyltransferases (53). The presence or absence of these transferases will determine some incidences of cancer (54). Attempts have been made to ascribe cancer incidences in different populations to acetyltransferase differences (55). 

One of the first pharmacogenetic traits to be recognized more than 50 years ago was the slow acetylation of the antituberculosis drug isoniazid now known as the polymorphism of /V-acety11ranslerasc 2 (NAT2) and inherited as an autosomal recessive trait (reviewed in Refs. 11 and 12). 

Orientals are fast acetylators. Separation of individuals into either rapid or slow acetylators is determined by variation at a single autosomal locus and constitutes one of the first discovered genetic polymorphisms of drug metabolism. In general, Eskimos are fast acetylators, while Jews and white North Africans are slow. The half-life of the acetylation reaction for isoniazid in fast acetylators is approximately 70 minutes, whereas in the slow acetylators this value is in excess of 3 hours. 

Genetic polymorphism found to influence isoniazid blood concentrations... 

Race and ethnicity may also be risk factors for ADRs. Prior personal or family history of ADRs may be predictive of future adverse reactions. Genetic polymorphisms for many metabolic reactions are described in Chapter 13 and have been well documented (45). Prescribing some medications without regard to genetic differences in metabolism can result in therapeutic failures or drug toxicity (45, 46). For example, differences in acetylator phenotype can alter the metabolism of some drugs and influence the risk of certain adverse reactions. Slow acetylators, for example, may be more likely than rapid acetylators to develop he pa to toxicity from isoniazid treatment. The biochemical basis for this difference is described in Chapter 16. 

Less commonly, variation is discontinuous when differences in response reveal a discrete proportion, large or small, who respond differently from the rest, e.g. poor drug oxidisers or fast and slow acetylators of isoniazid. Discontinuous variation most commonly occurs when response to a drug is controlled by a single gene. The term genetic polymorphism refers to the existence in a population of two or more discontinuous forms of a species which are subject to simple inheritance. By convention the frequency of each species is 1% or more. 

The acetylation pattern of several drugs (e.g.. Isoniazid. hydralazine, procainamide) in the human population displays a bimodal character in which the drug is conjugated either rapidly or slowly with acetyl-CoA. " This phenomenon is termed acetylation polymorphism. Individuals... 

Acetylation of drugs is also associated with genetically determined interindividual and interethnic differences. Differences in isoniazid toxicity between Asians and Caucasians are due to acetylation enzyme polymorphism. The majority (78%-93%) of Chinese and East Asians are fast acetylators, whereas only 50% of whites and African Americans are fast acetylators (Weber 1987). This is clinically important, because several psychoactive compounds (e.g., caffeine, clonazepam, nitrazepam, and phenelzine) are metabolized through acetylation (Sjoqvist et al. 1997). 

This polymorphism (NAT2) was discovered almost 50 years ago after differences were observed to isoniazid toxicity in tuberculosis patients (66). Subsequently, the differences in isoniazid toxicity were attributed to genetic variability in NAT2, a cytosolic phase II conjugation enzyme primarily responsible for deactivation of isoniazid (67). Indeed, the polymorphism was termed the "isoniazid acetylation polymorphism" for many years until the importance of the polymorphism in the metabolism and disposition of other drugs and chemical carcinogens was fully appreciated (65). 

Acetylation is a very common metabolic reaction, which occurs with amino, hydroxyl or sulfhydryl groups. The acetyl group is transferred from acetyl-Coenzyme A, and the reaction is catalyzed by acetyltransferases. An important aspect of this kind of substitution is the genetic polymorphism of one acetyltrans-ferase in humans, who are divided into fast and slow acetyla-tors. In a few cases, the conjugates are further metabolized to toxic compounds, as is seen with isoniazid. Some evidence exists that acetylation of the antitubercular isoniazid leads to enhanced hepatotoxicity of the drug. " Acetylation followed by hydrolysis and CYP-dependent oxidation yields free acetyl... 

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