Polymorphisms acetyltransferase

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. 

Grant DM, Blum M, Beer M, et al. Monomorphic and polymorphic human arylamine N-acetyltransferases a comparison of liver isozymes and expressed products of two cloned genes. Mol Pharmacol 1991 39(2) 184-191. 

L. W. Wormhoudt, J. N. Commandeur, N. P. Vermeulen, Genetic Polymorphisms of Human V-Acetyltransferase, Cytochrome P450, Glutathione 5-Transferase, and Epoxide Hydrolase Enzymes Relevance to Xenobiotic Metabolism and Toxicity , Crit. Rev. Toxicol. 1999, 29, 59 - 124. 

Similarly, polymorphisms on the A -acetyltransferase 1 and 2 genes (NATl, NAT2) that encode the enzymes responsible for inactivating 5-aminosalicylate and sulfapyridine did not influence response to therapy or toxicity (46). 

As their name implies, the A-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. Examples of this type of reaction are depicted in Figure 4.1. The net result of this conjugation is an increase in water solubility and increased elimination of the compound. The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2. Little overlap in substrate specificities of the two isoforms appears to exist. NAT-2 is a polymorphic enzyme, a... 

Grant DM, Blum M, Meyer UA. Polymorphisms of N-acetyltransferase genes. Xenobiotica 1992 22 1073. Human cytochrome P450s assessment, regulation and genetic polymorphisms. Xenobiotica, 28, number 12, 1998. A series of relevant articles. 

Huang Y-S, Chern HD, Su WJ, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for anti tuberculosis drug-induced hepatitis. Hepatology 2002 35 883-889. 

D.M. Grant, P. Vohra, Y. Avis, A. Ima, Detection of a New Polymorphism of Human Arylamine N-Acetyltransferase NAT1 Using / -Aminosalicylic Acid as an In Vivo Probe , /. Basic Clin. Physiol Pharmacol., 3(Suppl.), 244 (1992). 

Grant DM, Hughes NC, Janezic SA, Goodfellow GH, Chen HJ, Gaedigk A, Yu VL, Grewal R. Human acetyltransferase polymorphisms. Mutat Res 1997 376 61-70. 

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). 

Brockton N, Little J, Sharp L, Cotton SC. Y-acetyltransferase polymorphisms and colorectal cancer a HuGE review. Am J Epidemiol 2000 151 846-861. 

Gupta RC, Atul BV (2000) Drug metabolism studies in animal models. Ind 1 Pharmacol 32 S62-S66 Hassett C, Lin 1, Carty CL et al. (1997) Human hepatic microsomal epoxide hydrolase comparative analysis of polymorphic expression. Arch Biochem Biophys 337 275-283 Hengstler 1G, Arand M, Herrero ME, Oesch F (1998) Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfo-transferases influence on cancer susceptibility. Recent Results Cancer Res 154 47-85... 

Wormhoudt LW, Commandeur JN, Vermeulen NP (1999) Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 29 59-124... 

Hein, D. W. IV-Acetyltransferase 2 genetic polymorphism Effects of carcinogen and haplo-type on urinary bladder cancer risk. Oncogene 25, 1649-1658, 2006. 

Hengstler JG, Arand M, Herrero ME, Oesch F. Polymorphisms of N-acetyltransferases, glutathione S-transferases, microsomal epoxide hydrolase and sulfo-transferases Influence on cancer susceptibility. Recent Results Cancer Res 1998 154 47-85. 

Lin HJ, Han CY, Lin BK, Hardy S. Slow acety-lator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites Application to metabolic epidemiology. Am J Hum Genet 1993 52 827-34. 

Lee EJ, Zhao B, Seow-Choen F. Relationship between polymorphism of N-acetyltransferase gene and susceptibility to colorectal carcinoma in a Chinese population. Pharmacogenetics 1998 8 513-7. 

Ambrosone CB, Freud enheim JL, Graham S, Marshall JR, Vena JE, Brasure JR et al. Cigarette smoking, N acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 1996 276 1494-501. 

As discussed in Chapter 14/ genetic polymorphisms for the Phase I enzymes (CYP2D6 and CYP2C19) and the Phase II enzymes (N-acetyltransferase and the methyltransferases thiopurine methyltransferase/ catechol O-methyl transferase/ and thiol methyltransferase) may significantly alter exposure to relevant drug substrates. Evaluation of the frequency... 

---