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DOI: 10.1055/s-2007-963673
© Georg Thieme Verlag KG Stuttgart · New York
NAT1 Genotypes Do not Predict Response to Mesalamine in Patients with Ulcerative Colitis
NAT1-Genotypen erlauben keine Vorhersage für das Ansprechen auf Mesalamin bei Patienten mit Colitis ulcerosaPublication History
manuscript received: 14.5.2007
manuscript accepted: 16.10.2007
Publication Date:
06 March 2008 (online)
Zusammenfassung
Hintergrund: Die 5-Aminosalicylsäure (5-ASA) wird in der Darmmukosa von der N-Acetyltransferase 1 (NAT1) metabolisiert. Durch bekannte genetische Polymorphismen in diesem Enzym kommt es zu einer schnellen oder langsamen Acetylierung. Bei etwa 10 % der Patienten mit Colitis ulcerosa (CU) verursacht die Behandlung mit 5-ASA Nebenwirkungen. Wir haben daher die genetischen Variationen bei Patienten mit CU bestimmt und deren mögliche Assoziation mit dem klinischen Ansprechen auf 5-ASA untersucht. Methoden: Von 78 Patienten mit CU wurde DNA gewonnen. 77 % der Patienten befanden sich während der 5-ASA-Behandlung in Remission, 23 % litten an einem akuten Schub. Für 23 bekannte Allele wurde NAT1 mithilfe von RFLP-Untersuchungen und DANN-Sequenzierung genotypisiert. Retrospektiv wurde das dokumentierte klinische Ansprechen auf 5-ASA ermittelt und mit den NAT1-Genotypen korreliert. Ergebnisse: Mithilfe der PCR wurde eine 570-bp umfassende Region aus dem kodierenden Bereich und 240 bp aus der 3′-untranslatierten Region (UTR) des humanen NAT1-Gens amplifiziert. Dabei wurden die 4 bereits bekannten NAT1-Allele NAT1*3, *4, *10 und *11 gefunden. 31 % der Patienten waren heterozygot und 4 % homozygot für das NAT1*10-Allel. 6 % der Patienten waren heterozygot für das NAT1*3-Allel. 6 % waren heterozygot für das NAT1*11-Allel. Zwischen dem NAT1-Genotyp und dem klinischen Ansprechen beziehungsweise den Nebenwirkungen wurden keine Assoziationen gefunden. Schlussfolgerung: Die NAT1-Genotypen erlauben keine Vorhersage für das klinische Ansprechen von Patienten mit CU auf Mesalamin oder zu erwartende Nebenwirkungen. Das Ansprechen auf 5-ASA könnte daher auch durch nicht genomische Effekte beeinflusst werden.
Abstract
Background: 5- Aminosalicylic acid (5-ASA) is metabolised in colonic mucosa by N-acetyltransferase 1 (NAT1). Common genetic polymorphisms in this enzyme result in rapid or slow acetylation. 5-ASA treatment causes side effects in up to 10 % of patients with ulcerative colitis (UC). We therefore determined genetic variations of NAT1 in patients with UC and looked for a possible association with the clinical response to 5-ASA. Methods: DNA was obtained from 78 patients with UC. 77 % of the patients were in remission during 5-ASA treatment, whereas 23 % suffered from active disease. NAT1 genotyping was performed for 23 known alleles using RFLP and sequence analysis. Clinical response to 5-ASA was determined by medical record review and associated with NAT1 genotypes. Results: Utilising PCR we amplified a 570-bp coding region of the human NAT1 gene in addition to 240 bp in the 3′-untranslated region (UTR). 4 NAT1 alleles previously known as NAT1*3, *4, *10 and *11 were recovered. 31 % of the patients were heterozygous and 4 % homozygous for the NAT1*10 allele. 6 % were heterozygous for the NAT1*3 allele. 6 % were heterozygous for the NAT1*11 allele. No association was found between NAT1 genotype and clinical response as well as side effects to 5-ASA in patients with UC. Conclusions: NAT1 genotypes do not predict response or side effects to mesalamine in patients with UC. Variations caused by non-genomic effects may be associated with the clinical response to 5-ASA.
Schlüsselwörter
Colitis ulcerosa - Morbus Crohn - intestinale Komplikation
Key words
ulcerative colitis - Crohn’s disease - intestinal complications
References
- 1 Small R E, Schraa C C. Chemistry, pharmacology, pharmacokinetics, and clinical applications of mesalamine for the treatment of inflammatory bowel disease. Pharmacotherapy. 1994; 14 385-398
- 2 Easterbrook J, Armstrong G, Bayless T M. et al .Pharmacogenetics of 5ASA metabolism in IBD patients: Preliminary report of variation in N-acetyltransferase polymorphisms and 5ASA metabolism rates in mucosal biopsies. Annual Meeting of American Gastroenterological Association New Orleans Philadelphia; W B Saunder Company 1998
- 3 Zhou S Y, Fleisher D, Pao L H. et al . Intestinal metabolism and transport of 5-aminosalicylate. Drug Metab Dispos. 1999; 27 (4) 479-485
- 4 Jenne J W. Partial purification and properties of the isoniazid transacetylase in human liver. Its relationship to the acetylation of p-aminosalicylic acid. J Clin Invest. 1965; 44 (12) 1992-2002
- 5 Ilett K F, Ingram D M, Carpenter D S. et al . Expression of monomorphic and polymorphic N-acetyltransferases in human colon. Biochem Pharmacol. 1994; 47 (5) 914-917
- 6 Hein D W, Doll M A, Rustan T D. et al . Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions. Cancer Res. 1995; 55 (16) 3531-3536
- 7 Bell D A, Badawi A F, Lang N P. et al . Polymorphism in the N-acetyltransferase 1 (NAT1) polyadenylation signal: association of NAT1*10 allele with higher N-acetylation activity in bladder and colon tissue. Cancer Res. 1995; 55 (22) 5226-5229
- 8 Windmill K F, Gaedigk A, Hall P M. et al . Localization of N-acetyltransferases NAT1 and NAT2 in human tissues. Toxicol Sci. 2000; 54 (1) 19-29
- 9 Debiec-Rychter M, Land S J, King C M. Histological localization of acetyltransferases in human tissue. Cancer Lett. 1999; 143 (2) 99-102
- 10 Hickman D, Pope J, Patil S D. et al . Expression of arylamine N-acetyltransferase in human intestine. Gut. 1998; 42 (3) 402-409
- 11 Christensen L A, Fallingborg J, Abildgaard K. et al . Topical and systemic availability of 5-aminosalicylate: comparisons of three controlled release preparations in man. Aliment Pharmacol Ther. 1990; 4 (5) 523-533
- 12 Larouche J, Morais J, Picard M. et al . Release of 5-ASA from Pentasa in patients with Crohn’s disease of the small intestine. Aliment Pharmacol Ther. 1995; 9 (3) 315-320
- 13 Layer P H, Goebell H, Keller J. et al . Delivery and fate of oral mesalamine microgranules within the human small intestine. Gastroenterology. 1995; 108 1427-1433
- 14 Yu D K, Morrill B, Eichmeier L S. et al . Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man. Eur J Clin Pharmacol. 1995; 48 (3 - 4) 273-277
- 15 Deguchi T, Mashimo M, Suzuki T. Correlation between acetylator phenotypes and genotypes of polymorphic arylamine N-acetyltransferase in human liver. J Biol Chem. 1990; 265 (22) 12 757-12 760
- 16 Butcher N J, Ilett K F, Minchin R F. Functional polymorphism of the human arylamine N-acetyltransferase type 1 gene caused by C 190T and G 560A mutations. Pharmacogenetics. 1998; 8 (1) 67-72
- 17 Bruhn C, Brockmoller J, Cascorbi I. et al . Correlation between genotype and phenotype of the human arylamine N-acetyltransferase type 1 (NAT1). Biochem Pharmacol. 1999; 58 (11) 1759-1764
- 18 Payton M A, Sim E. Genotyping human arylamine N-acetyltransferase type 1 (NAT1): the identification of two novel allelic variants. Biochem Pharmacol. 1998; 55 (3) 361-366
- 19 Weber W W, Vatsis K P. Individual variability in p-aminobenzoic acid N-acetylation by human N-acetyltransferase (NAT1) of peripheral blood. Pharmacogenetics. 1993; 3 (4) 209-212
- 20 Hein D W, Rustan T D, Ferguson R J. et al . Metabolic activation of aromatic and heterocyclic N-hydroxyarylamines by wild-type and mutant recombinant human NAT1 and NAT2 acetyltransferases. Arch Toxicol. 1994; 68 (2) 129-133
- 21 Allgayer H, Ahnfelt N O, Kruis W. et al . Colonic N-acetylation of 5-aminosalicylic acid in inflammatory bowel disease. Gastroenterology. 1989; 97 (1) 38-41
- 22 Vatsis K P, Weber W W, Bell D A. et al . Nomenclature for N-acetyltransferases. Pharmacogenetics. 1995; 5 (1) 1-17
- 23 Grant D M, 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
- 24 Ozawa S, Abu-Zeid M, Kawakubo Y. et al . Monomorphic and polymorphic isozymes of arylamine N-acetyltransferases in hamster liver: purification of the isozymes and genetic basis of N-acetylation polymorphism. Carcinogenesis. 1990; 11 (12) 2137-2144
- 25 Hughes N C, Janezic S A, McQueen K L. et al . Identification and characterization of variant alleles of human acetyltransferase NAT1 with defective function using p-aminosalicylate as an in-vivo and in-vitro probe. Pharmacogenetics. 1998; 8 (1) 55-66
- 26 Schreiber S, Hamling J, Zehnter E. et al . Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate. Gut. 1997; 40 (6) 761-766
- 27 Ricart E, Taylor W R, Loftus E V. et al . N-acetyltransferase 1 and 2 genotypes do not predict response or toxicity to treatment with mesalamine and sulfasalazine in patients with ulcerative colitis. Am J Gastroenterol. 2002; 97 (7) 1763-1768
- 28 Hein D W, McQueen C A, Grant D M. et al . Pharmacogenetics of the arylamine N-acetyltransferases: a symposium in honor of Wendell W. Weber. Drug Metab Dispos. 2000; 28 (12) 1425-1432
- 29 Sim E, Payton M, Noble M. et al . An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes. Hum Mol Genet. 2000; 9 (16) 2435-2441
- 30 Deitz A C, Doll M A, Hein D W. A restriction fragment length polymorphism assay that differentiates human N-acetyltransferase-1 (NAT1) alleles. Anal Biochem. 1997; 253 (2) 219-224
- 31 Rasmussen S N, Bondesen S, Hvidberg E F. et al . 5-aminosalicylic acid in a slow-release preparation: bioavailability, plasma level, and excretion in humans. Gastroenterology. 1982; 83 1062-1070
- 32 Leon J H, Vatsis K P, Weber W W. Characterization of naturally occurring and recombinant human N-acetyltransferase variants encoded by NAT1. Mol Pharmacol. 2000; 58 (2) 288-299
- 33 Hein D W, Doll M A, Fretland A J. et al . Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev. 2000; 9 (1) 29-42
- 34 Cascorbi de I, Roots I, Brockmoller J. Association of NAT1 and NAT2 polymorphisms to urinary bladder cancer: significantly reduced risk in subjects with NAT1*10. Cancer Res. 2001; 61 (13) 5051-5056
Dr. Martin Hausmann
Abteilung für Gastroenterologie und Hepatologie, UniversitätsSpital Zürich
Rämisstrasse 100
8091 Zürich
Email: martin.hausmann@usz.ch