N-Acetyltransferase 2 Genotypes among Zulu-Speaking South Africans and Isoniazid and N-Acetyl-Isoniazid Pharmacokinetics during Antituberculosis Treatment

ABSTRACT The distribution of N-acetyltransferase 2 gene (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in the South African population is limited. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics (PK) in Zulu black HIV-infected South Africans in Durban, South Africa. HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Participants with culture-confirmed pulmonary TB were genotyped for the NAT2 polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A, and 803A>G using Life Technologies prevalidated TaqMan assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid and N-acetyl-isoniazid concentrations. Among the 120 patients, 63/120 (52.5%) were slow metabolizers (NAT2*5/*5), 43/120 (35.8%) had an intermediate metabolism genotype (NAT2*5/12), and 12/120 (11.7%) had a rapid metabolism genotype (NAT2*4/*11, NAT2*11/12, and NAT2*12/12). The NAT2 alleles evaluated in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C, and *12M. NAT2*5 was the most frequent allele (70.4%), followed by NAT2*12 (27.9%). Fifty-eight of 60 participants in study 1 had PK results. The median area under the concentration-time curve from 0 to infinity (AUC0–∞) was 5.53 (interquartile range [IQR], 3.63 to 9.12 μg h/ml), and the maximum concentration (Cmax) was 1.47 μg/ml (IQR, 1.14 to 1.89 μg/ml). Thirty-four of 40 participants in study 2 had both PK results and NAT2 genotyping results. The median AUC0–∞ was 10.76 μg·h/ml (IQR, 8.24 to 28.96 μg·h/ml), and the Cmax was 3.14 μg/ml (IQR, 2.39 to 4.34 μg/ml). Individual polymorphisms were not equally distributed, with some being represented in small numbers. The genotype did not correlate with the phenotype, with those with a rapid acetylator genotype showing higher AUC0–∞ values than those with a slow acetylator genotype, but the difference was not significant (P = 0.43). There was a high prevalence of slow acetylator genotypes, followed by intermediate and then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence isoniazid metabolism, and these warrant further investigation in this population.

Genetic Polymorphism of NAT2 Gene and its Association with Prostate Cancer

A N acetyltransferases 2 (NAT2) is one of the phase II metabolizing enzyme that participate in the bioconversion of heterocyclic arylamines into electrophilic nitrenium ions, which are important ultimate carcinogens that are directly implicated in tumor initiation process. Prostate epithelial cell express N acetyltransferases (NAT) enzymes and recent molecular epidemiological studies have analyzed the relationship between NAT2 in etiology of prostate cancer. A review by chen (2001) in prostate cancer (PCa) suggests that the frequencies of some polymorphisms in certain genes differ among different racial and ethnic groups. In a case control study in India by Srivastava and Mittal (2005), observed significant association between rapid acetylator genotype NAT2 and PCa in tobacco users (OR = 3.43, 95% CI: 1.68-7.02, p< 0.001) when compared with controls. Hamasaki et al (2003) in Japanese men, observed the frequency of the NAT slow acetylator genotype was statistically higher among prostate cancer patients (17.1%) compared with controls (8.6%). Another case control study in Turkey by Kosova et al. (2009), concluded that Nat2* 6A and NAT2 *7A/B gene polymorphism were significantly associated with prostate cancer. DOI: http://dx.doi.org/10.3329/akmmcj.v5i2.21131 Anwer Khan Modern Medical College Journal Vol. 5, No. 2: July 2014, Pages 39-42

Influence ofNAT2Polymorphisms on Sulfamethoxazole Pharmacokinetics in Renal Transplant Recipients

ABSTRACTThe sulfamethoxazole (SMX)-trimethoprim drug combination is routinely used as prophylaxis againstPneumocystispneumonia during the first 3 to 6 months after renal transplantation. The objective of this study was to examine the impact ofN-acetyltransferase 2 (NAT2) andCYP2C9polymorphisms on the pharmacokinetics of SMX in 118 renal transplant recipients. Starting on day 14 after renal transplantation, patients were administered 400 mg/day-80 mg/day of SMX-trimethoprim orally once daily. On day 14 after the beginning of SMX therapy, plasma SMX concentrations were determined by a high-performance liquid chromatography method. The SMX area under the concentration-time curve from 0 to 24 h (AUC0-24) for 15 recipients with theNAT2slow acetylator genotype (NAT2*5/*6, -*6/*6, -*6/*7, and -*7/*7) was significantly greater than that for 56 recipients with theNAT2rapid acetylator genotype (homozygous forNAT2*4) (766.4 ± 432.3 versus 537.2 ± 257.5 μg-h/ml, respectively;P= 0.0430), whereas there were no significant differences in the SMX AUC0-24between theCYP2C9*1/*1and -*1/*3groups. In a multiple regression analysis, the SMX AUC0-24was associated withNAT2slow acetylator polymorphisms (P= 0.0095) and with creatinine clearance (P= 0.0499). Hepatic dysfunction inNAT2slow acetylator recipient patients during the 6-month period after SMX administration was not observed. SMX plasma concentrations were affected byNAT2polymorphisms and renal dysfunction. Although standard SMX administration to patients withNAT2slow acetylator polymorphisms should be accompanied by monitoring for side effects and drug interaction effects from the inhibition of CYP2C9, SMX administration at a low dose (400 mg) as prophylaxis may not provide drug concentrations that reach the level necessary for the expression of side effects. Further studies with a larger sample size should be able to clarify the relationship between SMX plasma concentration and side effects.