Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis
ABSTRACT Antituberculosis drug-induced hepatitis attributed to isoniazide (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins.
To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients.
A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT2*5B), 590G to A (NAT2*6A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis.
Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P=0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT2*5B/5B and NAT2*6A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P=0.01, odds ratio [OR]=7.6 and P=0.029, OR=15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P=0.02, OR=0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P=0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P=0.01).
Our results suggest that the slow-acetylator status of NAT2 is risk factor for INH-induced hepatotoxicity. Moreover, diplotypes, NAT2*5B/5B, NAT2*6A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.
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ABSTRACT: Background: Our study aims to discuss the correlation between N-acetyltransferase 2 (NAT2) gene polymorphism and cirrhotic portal hypertension in the Chinese population for the purpose of exploring the functional significance of NAT2 gene polymorphism. Methods: From June 2010 to February 2014, a total of 212 posthepatitis B cirrhosis patients (the observation group) from the affiliated Shandong Province-owned Hospital of Shandong University diagnosed by needle biopsy of the liver, B ultrasound, or surgical operation were recruited. These 212 patients were divided into a cirrhotic portal hypertension group (PHT(+) group) (130 patients) and a simple liver cirrhosis (LC) group (PHT(-) group) (82 patients), and 172 healthy blood donors were enrolled into the control group. The polymerase chain reaction-restriction fragment length polymorphism method was adopted to detect NAT2 gene polymorphism and some related statistical analysis. Results: In these 212 patients, four mutation alleles in the NAT2 gene (WT, M1, M2, and M3) were detected. The frequency of patients carrying NAT2 slow acetylator genotype in the observation group was higher than that in the control group, but there was no significant difference (p>0.05). However, there was a significant difference in the NAT2 slow acetylator genotype frequency between the PHT(+) group and the control group (p<0.05). The risk for the occurrence of PHT in NAT2 slow acetylator genotype carriers was more frequent than that in NAT2 rapid acetylator genotype carriers. In addition, the diameters of the portal vein and splenic vein as well as spleen thickness in NAT2 rapid acetylator genotype were obviously bigger than that in the NAT2 slow acetylator genotype. Conclusions: Our study provided empirical evidence that NAT2 gene polymorphism may be correlated to the formation of cirrhotic portal hypertension, and it might be used as a potential biomarker for genetic susceptibility to PHT in Chinese population.Genetic Testing and Molecular Biomarkers 01/2015; 19(3). DOI:10.1089/gtmb.2014.0283 · 1.15 Impact Factor
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ABSTRACT: The clinical use of amifampridine phosphate for neuromuscular junction disorders is increasing. The metabolism of amifampridine occurs via polymorphic aryl N-acetyltransferase (NAT), yet its pharmacokinetic (PK) and safety profiles, as influenced by this enzyme system, have not been investigated. The objective of this study was to assess the effect of NAT phenotype and genotype on the PK and safety profiles of amifampridine in healthy volunteers (N = 26). A caffeine challenge test and NAT2 genotyping were used to delineate subjects into slow and fast acetylators for PK and tolerability assessment of single, escalating doses of amifampridine (up to 30 mg) and in multiple daily doses (20 mg QID) of amifampridine. The results showed that fast acetylator phenotypes displayed significantly lower Cmax, AUC, and shorter t1/2 for amifampridine than slow acetylators. Plasma concentrations of the N-acetyl metabolite were approximately twofold higher in fast acetylators. Gender differences were not observed. Single doses of amifampridine demonstrated dose linear PKs. Amifampridine achieved steady state plasma levels within 1 day of dosing four times daily. No accumulation or time-dependent changes in amifampridine PK parameters occurred. Overall, slow acetylators reported 73 drug-related treatment-emergent adverse events versus 6 in fast acetylators. Variations in polymorphic NAT corresponding with fast and slow acetylator phenotypes significantly affects the PK and safety profiles of amifampridine.02/2015; 3(1). DOI:10.1002/prp2.99
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ABSTRACT: Objective. Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne. Methods. Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012. Results. The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients. Conclusion. A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage.Thérapie 10/2014; 69(6). DOI:10.2515/therapie/2014202 · 0.40 Impact Factor