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  Current Drug Metabolism

Volume 9 Issue 6
ISSN: 1389-2002

 
   All Titles

Editorial [Hot Topic: N-Acetyltransferases: Lessons Learned from Eighty Years of Research (Guest Editor: Jose A.G. Agundez) ]
pp.463-464 (2) Author: Jose A.G. Agundez
 
Abstract:

During the past 80 years, research on Arylamine-Nacetyltransferases (CoASAc; NAT, EC 2.3.1.5) has produced many major discoveries that have helped scientists understand the basis for altered metabolism of drugs and xenobiotics.

The first references to the relevance of N-acetylation in humans date back to 1926 [1]. Nearly fifty years ago, Evans et al. demonstrated that acetylation of the isoniazid was bimodally distributed and that in vivo acetylation status was inheritable [2, 3]. The milestone work carried out by Meyer et al. in the Biozentrum of the University of Basel around 1990 caused a dramatic impulse in present knowledge of NAcetyltransferases. This work included the demonstration that common polymorphisms in human NAT2 result in a decreased level of protein in the liver [4], the partial purification of human NAT2 [5], the cloning of NAT1 and NAT2 [5, 6] and the functional analysis of recombinant expressed protein products [4]. Further developments in the role of polymorphisms on NAT2 activity were carried out by Hein et al. [7], and it is not surprising that the number of publications on N-acetyltransferases increased sharply from an average of 30-50 publications per year before 1990 to about 300 publications per year after 1991. Sinclair et al. in 2000 provided the first crystal structure of a NAT protein [8] and recently high resolution crystal structures of human NAT1 and NAT2 have been solved [9], revealing prominent features of NAT enzymes that will be of great help to further studies on structure, function and clinical relevance of NAT enzymes.

The complexity of variations in NAT1 and NAT2 genes has put NAT in the forefront of pharmacogenetics research. Four decades after the recognition and effect of NAT2 polymorphism on isoniazide toxicity [10], present genotyping techniques allow the detection of major genetic variations in these genes and permit acetylation phenotypes to be inferred from genotyping data by using bioinformatic tools [11]. The determination of the NAT2 genotype or phenotype was initially proposed to predict adverse reactions in patients with tuberculosis receiving isoniazid [12], before the concomitant administration of procainamide and phenytoin [13], and to analyze the role of NAT2 in drug interactions [14]. These effects together with the high frequency for individuals with impaired NAT2 metabolism [4] make NAT2 a relevant target for pharmacogenomic tests in clinical practice. Since NAT gene polymorphisms have been considered as putative risk factors for some xenobiotic-related cancers because of the prominent role of NAT enzymes in drug and carcinogen activation and detoxification, we can now take advantage of these pharmacogenomic tests to assess cancer risk and the risk of other human diseases. Presently, research on Arylamine- N-acetyltransferases constitutes a major topic in pharmacology and pharmacogenomics and has therapeutic, preventive, anthropologic and even forensic implications. The bibliometric impact of Arylamine-N-acetyltransferases is impressive. In recent years, over 5,000 papers related to drug acetylation and NAT polymorphisms have been published. These papers accumulate over 100,000 citations and an h-index over 120. Nowadays an average of six articles on this topic are published per week. This special issue of Current Drug Metabolism on Nacetyltransferases provides a collection of review articles covering relevant basic and clinical topics in which NATs are of prominent relevance. The articles presented summarize the present knowledge of these topics, and identify further aspects that should be investigated in detail.

The topics covered include the most recent advances in the structure of human NATs obtained after crystallization and direct structural analysis of human NAT1 and NAT2 as well as the potential applications of this information to the prediction of therapeutic and toxic effects [15]. A collection of papers related to genetic and non-genetic factors influencing NAT activities is also included in this special issue. The first of such papers is a comprehensive review of structure-function of variant NAT2 enzymes, including an analysis and molecular modeling of the effects of individual single nucleotide polymorphisms (SNPs) on NAT2 function and an update on NAT2 allele nomenclature [16]. The interethnic variability of human NAT2 SNPs, obtained after deconstruction of inferred variant alleles to avoid confounders, is analyzed in another paper that unravels the occurrence of intraethnic variability in NAT2 SNP frequencies and discusses the potential clinical impact of such intraethnic variability [17].

Affiliation: Department of Pharmacology Medical School University of Extremadura Avda. de Elvas s/n E-06071, Badajoz Spain.

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