Polymorphism of Human Acetyltransferases

Meyer, Urs

doi:10.2307/3432181

Cited by 9 publications

(9 citation statements)

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“…NAT1 is widely distributed in the organism, whereas NAT2 has a restricted tissue distribution with higher levels of expression in the liver and intestine (Meyer, 1994;Husain et al, 2007). N-acetyltransferases exhibit different substrate specificities; in humans, isoniazid and sulfamethazine are efficiently N-acetylated by NAT2, whereas p-aminobenzoic acid is a substrate for NAT1 (Meyer, 1994;Stevens et al, 1999). It is recognized that human NAT1 and NAT2 loci are highly polymorphic, with more than 25 alleles identified in each locus (Hein et al, 2000a,b;Stanley and Sim, 2008;Walraven et al, 2008).…”

mentioning

confidence: 99%

“…As an important metabolizing enzyme in humans, the polymorphisms in human NAT expression, especially NAT2, raise concerns about drug-drug interactions related to drug metabolism during clinical use (Spielberg, 1996;Dorne, 2004). Slow and rapid acetylators of both forms of NAT1 and NAT2 were identified in humans (Grant et al, 1991;Meyer, 1994). In addition to NAT polymorphisms, species differences in drug N-acetylation were also described (Glinsukon et al, 1975;Sharer et al, 1995;Gao et al, 2006), which could introduce interspecies variability in drug metabolism, raising concerns about the use of certain animal species for metabolic profiling of new compounds.…”

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confidence: 99%

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N-Acetylation of Etamicastat, a Reversible Dopamine-β-Hydroxylase Inhibitor

Loureiro¹,

Fernandes-Lopes²,

Bonifácio³

et al. 2013

Drug Metab Dispos

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Etamicastat [(R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione hydrochloride] is a reversible dopamineb-hydroxylase inhibitor that decreases norepinephrine levels in sympathetically innervated tissues. After in vivo administration, N-acetylation of etamicastat was found to be a main metabolic pathway. The purpose of the current study was to characterize the N-acetylation of etamicastat by N-acetyltransferases (NAT1 and NAT2) and evaluate potential species differences in etamicastat N-acetylation using a sensitive and specific liquid chromatographymass spectrometry assay. Marked differences in etamicastat N-acetylation were observed among the laboratory species and humans. After oral administration, the rat, hamster, and human subjects presented the highest rates of etamicastat N-acetylation, whereas almost no acetylation was observed in the mouse, rabbit, minipig, and monkey and no acetylation was observed in the dog.In in vitro studies, rats and humans showed similar acetylation rates, whereas no acetylation was detected in the dog. Studies performed with human recombinant NAT1 4 and NAT2 4 enzymes revealed that both were able to conjugate etamicastat, although at different rates. NAT1 had lower affinity compared with NAT2 (K m , 124.8 6 9.031 mM and 17.14 6 3.577 mM, respectively). A significant correlation (r 2 = 0.65, P < 0.05) was observed in a comparison of etamicastat N-acetylation by human single-donor enzymes and sulfamethazine, a selective substrate to NAT2. No correlation was observed with p-aminosalicylic acid, a NAT1 selective substrate. In conclusion, these results suggest that NAT2 and, to a lesser extent, NAT1 contribute to etamicastat N-acetylation. Furthermore, the high interspecies and intraspecies differences in N-acetylation should be taken into consideration when evaluating the in vivo bioavailability of etamicastat.

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confidence: 99%

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confidence: 99%

N-Acetylation of Etamicastat, a Reversible Dopamine-β-Hydroxylase Inhibitor

Loureiro¹,

Fernandes-Lopes²,

Bonifácio³

et al. 2013

Drug Metab Dispos

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“…The enzymes involved in their metabolism are interesting targets in studies for polymorphisms leading to interindividual differences in the activation/deactivation of these substances creating a unique genetic make-up for every individual (14)(15)(16). The interactions between the genetic make-up of an individual with these environmental factors may be reflected in the type and frequency of the observed somatic mutations in various types of cancer.…”

Section: Carcinogen-dna Interactions: Molecular Archeology Of Carcinomentioning

confidence: 99%

Challenges of genetic diversity and the use of high throughput genotyping in genetic epidemiology

Kristensen¹

2009

Nor J Epidemiol

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This paper provides a discussion of the challenges in studies of genetic variation in epidemiology represented by the vast complexity of genetic variation. Choices of design and targets of the right genetic markers could be essential for detection of genetic susceptibility. Identification of genetic variation that is likely to be involved in the biological pathway of a particular condition could be of vital importance. A review is given of current use of genetic variation of a series of genes (TP53, GST, CYP) in studies of genetic susceptibility. Approaches to studies of gene-environment interaction involving exposure to endocrine disrupters are discussed. Finally the paper discusses new developments in the methodology for high throughput genotyping. Such techniques are assumed to be of particular relevance for larger epidemiological studies.

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“…Special emphasis has been placed on a phase II metabolizing enzyme, N-acetyltransferase type 2 (Nat2, EC 2.3.1.5), a milestone in the pharmacogenetics field as one of the first enzymes to be associated as a cause of interindividual variation in drug metabolism [3]. Nat2 catalyzes a transfer of an acetyl group from the cofactor acetyl-coenzyme A (acetyl-CoA) to the amine nitrogen atom of aromatic amines and hydrazines [4].…”

Section: Introductionmentioning

confidence: 99%

Interethnic diversity of NAT2 polymorphisms in Brazilian admixed populations

et al. 2010

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BackgroundN-acetyltransferase type 2 (Nat2) is a phase II drug- metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines. Its relevance in drug metabolism and disease susceptibility remains a central theme for pharmacogenetic research, mainly because of its genetic variability among human populations. In fact, the evolutionary and ethnic-specific SNPs on the NAT2 gene remain a focus for the potential discoveries in personalized drug therapy and genetic markers of diseases. Despite the wide characterization of NAT2 SNPs frequency in established ethnic groups, little data are available for highly admixed populations. In this context, five common NAT2 SNPs (G191A, C481T, G590A, A803G and G857A) were investigated in a highly admixed population comprised of Afro-Brazilians, Whites, and Amerindians in northeastern Brazil. Thus, we sought to determine whether the distribution of NAT2 polymorphism is different among these three ethnic groups.ResultsOverall, there were no statistically significant differences in the distribution of NAT2 polymorphism when Afro-Brazilian and White groups were compared. Even the allele frequency of 191A, relatively common in African descendents, was not different between the Afro-Brazilian and White groups. However, allele and genotype frequencies of G590A were significantly higher in the Amerindian group than either in the Afro-Brazilian or White groups. Interestingly, a haplotype block between G590A and A803G was verified exclusively among Amerindians.ConclusionsOur results indicate that ethnic admixture might contribute to a particular pattern of genetic diversity in the NAT2 gene and also offer new insights for the investigation of possible new NAT2 gene-environment effects in admixed populations.

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Polymorphism of Human Acetyltransferases

Cited by 9 publications

References 13 publications

N-Acetylation of Etamicastat, a Reversible Dopamine-β-Hydroxylase Inhibitor

N-Acetylation of Etamicastat, a Reversible Dopamine-β-Hydroxylase Inhibitor

Challenges of genetic diversity and the use of high throughput genotyping in genetic epidemiology

Interethnic diversity of NAT2 polymorphisms in Brazilian admixed populations

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