NAT2 global landscape: Genetic diversity and acetylation statuses from a systematic review

Abstract

Arylamine N-acetyltransferase 2 has been related to drug side effects and cancer susceptibility; its protein structure and acetylation capacity results from the polymorphism’s arrays on the NAT2 gene. Absorption, distribution, metabolism, and excretion, cornerstones of the pharmacological effects, have shown diversity patterns across populations, ethnic groups, and even interethnic variation. Although the 1000 Genomes Project database has portrayed the global diversity of the NAT2 polymorphisms, several populations and ethnicities remain underrepresented, limiting the comprehensive picture of its variation. The NAT2 clinical entails require a detailed landscape of its striking diversity. This systematic review spans the genetic and acetylation patterns from 164 articles from October 1992 to October 2020. Descriptive studies and controls from observational studies expanded the NAT2 diversity landscape. Our study included 243 different populations and 101 ethnic minorities, and, for the first time, we presented the global patterns in the Middle Eastern populations. Europeans, including its derived populations, and East Asians have been the most studied genetic backgrounds. Contrary to the popular perception, Africans, Latinos and Native Americans have been significantly represented in recent years. NAT2*4, *5B, and *6A were the most frequent haplotypes globally. Nonetheless, the distribution of *5B and *7B were less and more frequent in Asians, respectively. Regarding the acetylator status, East Asians and Native Americans harboured the highest frequencies of the fast phenotype, followed by South Europeans. Central Asia, the Middle East, and West European populations were the major carriers of the slow acetylator status. The detailed panorama presented herein, expands the knowledge about the diversity patterns to genetic and acetylation levels. These data could help clarify the controversial findings between acetylator states and the susceptibility to diseases and reinforce the utility of NAT2 in precision medicine.

Pharmacokinetics and pharmacodynamics of high-dose isoniazid for the treatment of rifampicin- or multidrug-resistant tuberculosis in Indonesia

“…Compared with a previous study in adults with MDR-TB in South Africa given 10 mg/kg doses, plasma isoniazid exposures in our study are slightly lower, both for AUC 0–24 (geometric mean 35.4 versus mean 45.7 h·mg/L) and C max (geometric mean 8.5 versus mean 9.4 mg/L). 12 As noted in a recent systematic review, this phenomenon might be explained by the high frequency of the fast acetylator phenotype in people originating from specific geographical regions, notably East Asia (including Indonesia), compared with those from Central Asia, sub-Saharan Africa and West Europe, who are the main carriers of the slow acetylator status, 31 although this finding is not confirmed in some studies in sub-Saharan Africa, where ∼60% of patients demonstrate the intermediate/fast acetylator phenotype. 23 , 29 …”

Corrected speciation and gyromitrin content of false morels linked to ALS patients with mostly slow-acetylator phenotypes

“…The presence of other ALS patients with a predicted intermediate ( n = 1/7) or fast ( n = 2/7) NAT2 genotype suggests rapid metabolism of gyromitrin is not necessarily protective. A detailed description of the global geographical (including France) and ethnic diversity of NAT2 genotypes has been published recently [ 8 ].…”

Efficacy, safety, and pharmacokinetics of isoniazid affected by NAT2 polymorphisms in patients with tuberculosis: A systematic review

“…3 Polymorphisms in the NAT2 gene significantly influence the activity of the enzyme, leading to interindividual variation in drug metabolism and susceptibility to certain diseases such as TB. 4 NAT2 activity is classified into three main categories: rapid (RA), intermediate (IA), and slow (SA) acetylators. The SA type results in reduced NAT2 enzyme activity and slower INH metabolism compared with the RA or IA types, leading to higher INH plasma concentrations, prolonged exposure to the drug and an increased risk of INH toxicity, especially hepatotoxicity.…”

“…INH is primarily inactivated in the liver and intestine by acetylation, a process catalyzed by the phase II enzyme N‐acetyltransferase 2 (NAT2) 3 . Polymorphisms in the NAT2 gene significantly influence the activity of the enzyme, leading to interindividual variation in drug metabolism and susceptibility to certain diseases such as TB 4 …”

“… 3 Polymorphisms in the NAT2 gene significantly influence the activity of the enzyme, leading to interindividual variation in drug metabolism and susceptibility to certain diseases such as TB. 4 …”