Differences in N-acetylation genotypes between Caucasians and Black South Africans: implications for cancer prevention

Loktionov, Alexandre; Moore, William; Spencer, Steven P.; Vorster, Hester H.; Nell, Theo; O'Neill, I.K.; Bingham, Sheila

doi:10.1016/s0361-090x(02)00010-7

Cited by 46 publications

(40 citation statements)

References 31 publications

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“…The distribution of the NAT1 and NAT2 alleles and haplotypes in our mixed-race patients and a small number of black patients is similar to that reported in previous studies of southern African populations (23,24). The allele frequencies adhere to HardyWeinberg equilibrium.…”

Section: Resultssupporting

confidence: 88%

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

Kock

Diacon

et al. 2015

Antimicrob Agents Chemother

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h The aim of this study was to examine the relationships between N-acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para-aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients' NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3, NAT1*14, and NAT2*5 alleles corresponded to 25, 37, ؊17, ؊48, and ؊27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele. p ara-Aminosalicylic acid (PAS) was the first effective antituberculosis agent used to treat pulmonary tuberculosis (1); for a duration of 20 to 25 years, it was part of the standard "first-line" tuberculosis treatment (2). Valued for preventing resistance in companion drugs, it was nonetheless notorious for gastrointestinal intolerance, causing frequent nausea, vomiting, and abdominal discomfort. The replacement of PAS with rifampin and ethambutol was greeted with relief by patients, but with widespread multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in a number of countries, particularly in the developing world, PAS is again being used to treat drug-resistant tuberculosis.The PAS preparation most commonly used in many countries is the granular slow-release (delayed-release) formulation (GSR-PAS), which prevents premature drug release in the stomach, avoiding the high PAS concentrations considered prone to cause intolerance. Several studies (3-7) have reported PAS concentrations associated with use of GSR-PAS in dosages from 4 g daily to 8 to 12 g daily in divided doses, as recommended by the World Health Organization (8). As PAS is usually considered bacteriostatic, divided dosing aims to provide concentrations consistently exceeding the PAS MIC of approx...

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Section: Resultssupporting

confidence: 88%

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

Kock

Diacon

et al. 2015

Antimicrob Agents Chemother

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“…NAT2 gene polymorphisms vary widely between regions (38). Rapid acetylator genotypes are reported to occur in about 60% of South Africans (17,34), but NAT2 genotype frequencies have not been reported among patients of Zulu ethnicity, which the majority of participants in our study represent. Interestingly, Kenyans were found to have similarly low isoniazid concentrations (7).…”

Section: Discussioncontrasting

confidence: 53%

Reduced Antituberculosis Drug Concentrations in HIV-Infected Patients Who Are Men or Have Low Weight: Implications for International Dosing Guidelines

McIlleron

Rustomjee

Vahedi

et al. 2012

Antimicrob Agents Chemother

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.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC 0-12 s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered.

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“…Striking ethnic differences in the frequencies of SNPs and genotypes (http://snp500cancer.nci.nih.gov) are responsible for the corresponding ethnic differences in the frequency of rapid ( Figure 5) and slow ( Figure 6) acetylator NAT2 alleles or haplotypes and therefore Figure 5 Rapid acetylator NAT2 allelic (haplotype) frequencies reported in various populations. Data for each population was derived from the following sources: Germany , Spain (Agundez et al, 1996), United Kingdom (UK), (Loktionov et al, 2002), Poland (Lan et al, 2003), Holland (van der Hel et al, 2003), USA Caucasian (Deitz et al, 2000), Nigeria (unpublished data from author's laboratory), South Africa (Loktionov et al, 2002), Africa (Delomenie et al, 1996), USA Black (O'Neill et al, 2000), South India (Anitha and Banerjee, 2003) and Korea (Lee et al, 2002).…”

Section: Molecular Geneticsmentioning

confidence: 99%

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

2006

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A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and diarylamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for the interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications.

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Differences in N-acetylation genotypes between Caucasians and Black South Africans: implications for cancer prevention

Cited by 46 publications

References 31 publications

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

Reduced Antituberculosis Drug Concentrations in HIV-Infected Patients Who Are Men or Have Low Weight: Implications for International Dosing Guidelines

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

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