N -acetylator, phenotype

Carrillo, J. and Benitez, J., Caffeine metabolism in a healthy Spanish population N-Acetylator phenotype and oxidation pathways. Clinical Pharmacological Therapeutics 55, 293-304, 1994. 

Dose Individualization of Amonafide Based on N-Acetylator Phenotype... 

Baud-Camus F, Marquet P, Soursac M et at. (2001) Determination of N-acetylation phenotype using caffeine as a metabolic probe and high-performance liquid chromatography with either ultraviolet detection or electrospray mass spectrometry. J Chromatogr B 760 55-63... 

Finally, polymorphisms associated with arylamine N-acetyltransferase (NAT2) may result in slow acetylators. The slow-acetylator phenotype is present in 50-70% of the population in Western countries and is associated with several drug-induced side effects. The frequency of the slow-acetylator phenotype rises to 80% in Egyptian and certain Jewish populations however, the frequency drops to 10% or 20% among Japanese and Canadian Eskimos. 

Consequence prolonged respiratory paralysis on exposure to the drug Suxamethonium (succinylcholine) for muscle relaxation for anesthesia Slow acetylator phenotype, due to mutations in liver N-acetylase transferase,... 

There is no information regarding the metabolism of 3,3 -dichlorobenzidine in children. However, N-acetylation (as discussed above) in humans is likely done by one of two families of N-acetyltransferases. One of these families, NAT2, is developmentally regulated (Leeder and Kearns 1997). Some enzyme activity can be detected in the fetus by the end of the first trimester. Almost all infants exhibit the slow acetylator phenotype between birth and 2 months of age. The adult phenotype distribution is reached by the age of 4-6 months, whereas adult activity is found by approximately 1-3 years of age. Also, UDP-glucuronosyltransferase, responsible for the formation of glucuronide conjugates, seems to achieve adult activity by 6-18 months of age (Leeder and Kearns 1997). These data suggest that metabolism of 3,3 -dichlorobenzidine by infants will differ from that in adults in extent, rate, or both. 

Woosley RL, Drayer DE, Reidenberg MM, Nies AS, Carr K, Oates JA. Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. N Engl J Med 1978 298 1157-1159. 

Meisel P, Schroeder C, Wulff K, Siegmund W (1997) Relationship between human genotype and phenotype of N-acetyltransferase (NAT2) as estimated by discriminant analysis and multiple linear regression 1.Genotype and N-acetylation in vivo. Pharmacogenetics 7 241-246... 

Rothen JP, Haefeli WE, Meyer UA et al. (1998) Acetominophen is an inhibitor of hepatic N-acetyltransferase 2 in vitro and in vivo. Pharmacogenetics 8 553-559 Tang BK, Kadar D, Qian L et al. (1991) Caffeine as a metabolic probe validation of its use for acetylator phenotyping. Clin Pharmacol Ther 49 648-657... 

Callicott JH, Egan MF, Bertolino A, Mattay VS, Langheim FJ, et al. 1998. Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia A possible intermediate neurobiological phenotype. Biol Psychiatry 44 941 -950. 

Individuals also vary widely in their elimination kinetics of isoniazid, procainamide, and other substrates of N-acetyltransferase (NAT2). Peripheral neuropathy associated with the use of isoniazid, an antituberculosis drug, first surfaced more than 40 years ago. It is now known that the slow acetylator phenotype represents approximately 40-50% of Caucasians, and results in decreased clearance of drug with increased potential for associated toxicities. 

One common polymorphism in the United States is for N-acetyltransferase, an enzyme involved in phase II reactions. N-acetyltransferase catalyzes the acetylation of aromatic amines and hydrazines, and other classes of xenobiotics. People characterized as slow acetylators have relatively low N-acetytransf-erase activity. Consequently, slow acetylators are more sensitive to the toxic effects of certain types of drugs, including sulfa drugs. In addition, a study of workers exposed to benzidine in the dye industry suggested a link between the slow acetylator phenotype and the development of bladder cancer. 

The N-acetyl transferase (NAT) polymorphism is one of the earliest pharmacogenetic targets recognized and characterized. NATs are Phase II enzymes that catalyze the transfer. of an acetyl moiety from acetyl-CoA to homocychc and heterocyclic arylamines and hydrazines. Substrates include drugs, carcinogens, toxicants, and possibly endogenous compounds. Slow metabolizer phenotypes, which may affect up to 90% of some populations, are manifested by changes in protein expression, protein stability, and enzyme kinetics. 

Das KM, Eastwood MA, McManus JP, Sircus W (1973) Adverse reactions during salicylazo-sulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 289 491-495... 

N-Acetyltransierase-2. TheJV-acetyl-transferase-2 (NAT2) polymorphism is one of the most common polymorphisms known in human populations. While more than 50% of Caucasians are NAT2 slow acetylator phenotype, there is a tremendous amount of interethnic variation in the frequency of the slow acetylator polymorphism (64). For instance, the slow acetylator phenotype is much more frequent in Egyptians but is much less frequent in Asians (65). 

The genetic polymorphism controlling N-acetylation may be demonstrated readily in human populations, where the distribution of the phenotypes shows marked ethnic variability (22) ... 

Genetic factors are particularly important in humans and can influence the response to the compound or the disposition of the compound and hence its toxicity. Several genetic factors affecting metabolism are known in which a non-functional or less functional form of the enzyme is produced in a particular phenotype, e.g. acetylator phenotype (N-acetyltransferase NAT2) hydroxylator status (cytochrome P-450 2D6) esterase deficiency (pseudocholinesterase). 

Wilkens, L.R., Pierce, L.M., Franke, A., Kolonel, L.N., Seifried, A., Custer, L.J., Chang, W., Lum-)ones, A., and Donlon, T. (2001) Combined effeds of well-done red meat, smoking, and rapid N-acetyl-transferase 2 and CYP1A2 phenotypes in increasing coloredal cancer risk. Cancer Epidemiol. Biomarkers Prev., 10, 1259-1266. 

Arylamine N-acetyltransferases (NAT) are highly conserved in eukaryotes. These cytosolic enzymes transfer acetate from acetylCoA to primary amines, hydrazines, sulfonamides, and aromatic amines. They are 30 to 34 kDa in size. Humans express two functional NATs, NATl and NAT2. The genes for both isoforms encode 290 amino acids, and are found on chromosome 8. Their nucleotide sequences share 87% homology. These enzymes exhibit polymorphism, and allelic variation especially for NAT2 is associated with fast and slow acetylator phenotypes. 

The discovery of polymorphic N-acetylation was linked to observations on the safety, metabolism, and pharmacokinetics of the antitubercular drug, isoniazid. When urinary excretion of isoniazid was evaluated in identical twins, fraternal twins, and unrelated subjects, the variability in its excretion depended upon genetic similarity. Ultimately, in a classic experiment by Evans and colleagues that measured the plasma isoniazid concentration in subjects who had taken a single 10 mg/kg dose of isoniazid, a clear polymorphic frequency distribution was revealed with an antimode of 2.5 ug/mL. Thus, two acetylator phenotypes were identified, and the slow acetylator phenotype had a frequency of 52%, and was an autosomal recessive trait. The slow acetylator phenotype, if treated with isoniazid (INH) is at increased risk of INH-induced arthralgias, neuropathy, and hepatotoxicity. 

Svensson, C. K., Sc Hein, D. W. (2005). Phenotypic and genotypic characterization of N-acetylation. In L. H. Lash (Ed.), Drug Metabolism and Transport Molecular Methods and Mechanisms (pp. 173—196). Totowa, Humana Press. 

First-pass acetylation in the Gl mucosa and liver is related to genetic acetylator phenotype (8). Acetylation phenotype is an important determinant of the plasma concentrations of hydralazine when the same dose of hydralazine is administered orally. Slow acetylators have an autosomal recessive trait that results in a relative deficiency of the hepatic enzyme N-acetyl transferase, thus prolonging the elimination half-life of hydralazine (see Chapter 10). This population of hypertensive patients will require an adjustment in dose to reduce the increased overactive response. Approximately 50% of African Americans and Caucasians, and the majority of American Indians, Eskimos, and Orientals are rapid acetylators of hydralazine. This population of patients will have subtherapeutic plasma concentrations of hydralazine because of its rapid metabolism to inactive metabolites and shorter elimination times. Patients with hydralazine-induced systemic lupus erythematosus frequently are slow acetylators. 

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