Status Asetilator Gen NAT2 pada Pasien Tuberkulosis dan Tuberkulosis dengan Diabetes Melitus di Kupang, Nusa Tenggara Timur

Alvinsyah Adhityo Pramono, Simeon Penggoam, Edhyana Sahiratmadja, Novi Vicahyani Utami, Tri Hanggono Achmad, Ramdan Panigoro

Abstract


Indonesia adalah negara dengan jumlah penderita tuberkulosis (TB) terbanyak kedua  di dunia. Diabetes melitus (DM) merupakan salah satu komorbid TB. Arylamine N-acetyltransferase 2 (NAT2) adalah enzim yang berfungsi memetabolisir isoniazid (INH) yang disandi oleh gen NAT2. Gen NAT2 memiliki sejumlah polimorfisme dan dapat menentukan kemampuan seseorang untuk memetabolisir obat yang disebut status asetilator. Pada individu dengan status asetilator lambat, INH dimetabolisir dengan lambat sehingga memungkinkan terjadi intoksikasi hati. Pada TB dengan DM (TBDM) status asetilator lambat dapat membuat pengobatan TB maupun DM menjadi kurang optimal. Penelitian ini bertujuan mengeksplorasi status asetilator pasien TBDM di RSUD Prof. WZ Johannes Kupang periode Juni–November 2011. Pada penelitian potong lintang ini DNA dari darah 122 pasien TB diisolasi dan gen NAT2 kemudian diamplifikasi dan disekuensing untuk diketahui status asetilatornya. Hasil penelitian menunjukkan terdapat 5 pasien yang memiliki glukosa serum >200 mg/dL yang dikategorikan sebagai pasien TBDM. Pada pasien TBDM didapatkan seorang dengan status asetilator cepat (NAT2*4/NAT2*4), 2 orang dengan status asetilator sedang (NAT2*13A/NAT2*6J), dan 2 orang dengan status asetilator lambat (NAT2*5/NAT2*5G, NAT2*6A/ NAT2*6A, NAT2*7B/ NAT2*7B). Pada pasien TB yang dipilih secara random berdasar usia dan jenis kelamin serupa dengan TBDM didapatkan 2 orang dengan status asetilator cepat (NAT2*4/NAT2*4) dan 3 orang dengan asetilator sedang (NAT2*4/NAT2*6A, NAT2*13A/NAT2*6J). TBDM yang memiliki status asetilator lambat berpotensi memiliki masalah ganda dalam terapi, selain dapat terjadi toksisitas hati akibat terapi dengan INH, juga dapat mengakibatkan pengobatan DM menjadi tidak optimal. Perlu dilakukan peneltian lebih lanjut terkait farmakogenetik pada TBDM. [MKB. 2016;49(1):61–6]

Kata kunci: Asetilator, isoniazid, NAT2, farmakogenetik, tuberkulosis

 

NAT2 Gene Acetylator Status of Tuberculosis and Tuberculosis with Diabetes Mellitus Patients in Kupang, Nusa Tenggara Timur

Indonesia is the second highest country with TB patients in the world. Diabetes mellitus (DM) is a comorbid of TB. Arylamine N-acetyltransferase 2 (NAT2), encoded by the NAT2 gene, is an enzyme that metabolizes isoniazid (INH). NAT2 gene has some polimorphysims that may play a role in INH acetylating process. Those who are slow acetylators may develop liver intoxication as a consequence of slow INH metabolism process. Slow acetylator TBDM patients may complicate both TB and DM treatment, causing them to be less optimal. The aim of this study was to explore the acetylator status of TBDM patients in Kupang, Indonesia. A cross-sectional study was conducted by obtaining DNA of 122 TB patients in Kupang in June–November 2011. NAT2 gene was amplified and sequenced to determine the acetylator status. There were 5 TB patients who had a glucose serum level of >200mg/dL and was catagorized as TBDM. Result showed that there was 1 TBDM patient who was a rapid acetylator (NAT2*4/NAT2*4), 2 patients as intermediate acetylators (NAT2*13A/NAT2*6J), and 2 patients as slow acetylators (NAT2*5/NAT2*5G, NAT2*6A/ NAT2*6A, NAT2*7B/ NAT2*7B). Meanwhile,  there were 2 TB patients who was rapid acetylators (NAT2*4/NAT2*4) and 3 patients as intermediate acetylators (NAT2*4/NAT2*6A, NAT2*13A/NAT2*6J). Slow NAT2 acetylator TBDM patients potentially face more problems during therapy. As INH may cause liver intoxication, these patients may also experience unoptimum DM treatment. Therefore, it is strongly recommended to do a study on the role of pharmacogenomics in TBDM. [MKB. 2016;49(1):61–6]

Key words: Acetylator, isoniazid, NAT2, pharmacogenetics, tuberculosis

 

DOI: 10.15395/mkb.v49n1.989


Keywords


Asetilator, isoniazid, NAT2, farmakogenetik, tuberkulosis

Full Text:

PDF

References


Sim E, Walters K, Boukouvala S. Arylamine N-acetyltransferases: from structure to function. Drug Metab Rev. 2008;40(3):479-510.

Sim E, Lack N, Wang CJ, Long H, Westwood I, Fullam E, dkk. Arylamine N-acetyltransferases: structural and functional implications of polymorphisms. Toxicology. 2008;254(3):170–83.

Sabbagh A, Langaney A, Darlu P, Gérard N, Krishnamoorthy R, Poloni ES. Worldwide distribution of NAT2 diversity: implications for NAT2 evolutionary history. BMC Genet. 2008;9(1):21.

Yuliwulandari R, Sachrowardi Q, Nishida N, Takasu M, Batubara L, Susmiarsih TP, dkk. Polymorphisms of promoter and coding regions of the arylamine N-acetyltransferase2 (NAT2) gene in the Indonesian population: proposal for a new nomenclature. J Hum Genet. 2008;53(3):201–9.

Alisjahbana B, van Crevel R, Sahiratmadja E, den Heijer M, Maya A, Istriana E, dkk. Diabetes mellitus is strongly associated with tuberculosis in Indonesia. Int J Tuberc Lung Dis. 2006;10(6):696–700.

Yalin S, Hatungil R, Tamer L, Ates NA, Dogruer N, Yildirim H, dkk. N-acetyltransferase 2 polymorphism in patients with diabetes mellitus. Cell Biochem Funct. 2007;25(4):407–11.

Kementerian Kesehatan RI. Riset Kesehatan Dasar RISKESDAS 2013. Jakarta: Kementerian Kesehatan RI; 2013.

Irshaid YM, Abujbara MA, Ajlouni KM, El-Khateeb M, Jarrar YB. N-acetyltransferase-2 genotypes among Jordanian patients with diabetes mellitus. Int J Clin Pharmacol Ther. 2013;51(7):593–9.

Boukouvala S, Hein DW, Grant DM, Sim E, Minchin RF, Agúndez JAG, dkk. Human NAT2 Alleles (Haplotypes) 2013 [diunduh 20 Oktober 2014]. Tersedia dari: http://nat.mbg.duth.gr/. Web.

Hein DW, Boukouvala S, Grant DM, Minchin RF, Sim E. Changes in consensus arylamine N-acetyltransferase gene nomenclature. Pharmacogenet Genomics. 2008;18(4):367–8.

Zang Y, Doll MA, Zhao S, States JC, Hein DW. Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2. Carcinogenesis. 2007;28(8):1665–71.

Ayieko J, Abuogi L, Simchowitz B, Bukusi EA, Smith AH, Reingold A. Efficacy of isoniazid prophylactic therapy in prevention of tuberculosis in children: a meta-analysis. BMC Infect Dis. 2014;14:91.

Hein DW. N-acetyltransferase SNPs: emerging concepts serve as a paradigm for understanding complexities of personalized medicine. Expert Opin Drug Metab Toxicol. 2009;5(4):353–66.

Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet. 2012;27(1):9–54.

Cavaco I, Asimus S, Peyrard-Janvid M, Ferreira PE, Veiga MI, Hai TN, dkk. The Vietnamese Khin population harbors particular N-acetyltransferase2 allele frequencies. Clin Chem. 2007;53(11):1977–9.


Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.


 

This Journal indexed on:

             


Creative Commons License
MKB is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

 


View My Stats