Genetic variants of N-acetyltransferases 1 and 2 (NAT1 and NAT2) in cynomolgus and rhesus macaques

Uno, Yasuhiro; Murayama, Norie; Yamazaki, Hiroshi

doi:10.1016/j.bcp.2020.113996

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…The acetyl-CoA-dependent acetylations at substrate concentrations of 30 µM and 300 µM of p-aminobenzoic acid, 2-aminofluorene, sulfamethazine, and isoniazid (Uno et al, 2020) were determined using a reversed-phase liquid chromatography as described previously (Uno et al, 2018). Typical reaction mixtures of 200 µL containing NAT protein (40 pmol equivalents/mL) or liver cytosolic fractions from marmosets, pigs, and humans (0.40 mg/mL), each substrate, and 1 mM dithiothreitol in 20 mM sodium phosphate buffer (pH 8.0) were initiated by the addition of acetyl-CoA (1.0 mM).…”

Section: Enzyme Assaysmentioning

confidence: 99%

“…For example, R64W reduces the enzymatic activity of NAT1 and NAT2, and D122N inactivates NAT2 (Walraven et al, 2008b;Hein, 2009). Similarly, in cynomolgus macaques, D122N reduces NAT1 activity, and 6 T98A reduces NAT2 activity (Uno et al, 2020). NATs represent an early example of pharmacogenetic variation and established the basis of understanding variability in drug metabolism among different populations (Sim et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Molecular and Functional Characterization of N-Acetyltransferases in Common Marmosets and Pigs

et al. 2022

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Arylamine N-acetyltransferases (NATs) are drug-metabolizing enzymes essential for the metabolism of endogenous substrates and xenobiotics. The molecular characteristics of NATs have been extensively investigated in humans but remain to be investigated in common marmosets and pigs, animal species that are often used in drug metabolism studies. In this study, marmoset NAT1 and pig NAT1 cDNAs were isolated from liver samples and were characterized by molecular analyses and drug-metabolism assays. These NAT genes were intronless and formed gene clusters with one other NAT gene in the genome, just as human NAT genes do. Marmoset NAT1 and pig NAT1 amino acid sequences showed high sequence identities (94% and 85%, respectively) to human NAT1. Phylogenetic analysis indicated that marmoset NAT1 and pig NAT1 were more closely clustered with human NATs than with rat or mouse NATs. Marmoset NAT1 and pig NAT1 mRNAs were expressed in all the tissue types analyzed, with the expression levels being highest in small intestine. Metabolic assays using recombinant proteins found that marmoset NAT1 and pig NAT1 metabolized human NAT substrates p-aminobenzoic acid, 2-aminofluorene, sulfamethazine, and isoniazid. Marmoset NAT1 and pig NAT1 substantially acetylated p-aminobenzoic acid and 2-aminofluorene relevant human NAT1, but their activities were lower toward sulfamethazine and isoniazid than those of the relevant human NAT2. Therefore, marmoset and pig NATs are functional enzymes with molecular similarities to human NAT1, but their substrate specificities, while similar to human NAT1, differ somewhat from human NAT2.

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Section: Enzyme Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular and Functional Characterization of N-Acetyltransferases in Common Marmosets and Pigs

et al. 2022

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“…NAT1 is expressed in many tissues but NAT2 is expressed predominantly in the liver and the gut. Homologs of human NATs have been isolated from rodents [ 203 , 204 ], hamsters [ 204 ] and New World monkeys [ 205 , 206 ]. Thus far, these enzymes have not been isolated from the common marmoset.…”

Section: Drug Metabolism Studies With Marmoset Esc-derived Hlcsmentioning

confidence: 99%

Utility of Common Marmoset (Callithrix jacchus) Embryonic Stem Cells in Liver Disease Modeling, Tissue Engineering and Drug Metabolism

Aravalli

Steer

2020

Genes

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The incidence of liver disease is increasing significantly worldwide and, as a result, there is a pressing need to develop new technologies and applications for end-stage liver diseases. For many of them, orthotopic liver transplantation is the only viable therapeutic option. Stem cells that are capable of differentiating into all liver cell types and could closely mimic human liver disease are extremely valuable for disease modeling, tissue regeneration and repair, and for drug metabolism studies to develop novel therapeutic treatments. Despite the extensive research efforts, positive results from rodent models have not translated meaningfully into realistic preclinical models and therapies. The common marmoset Callithrix jacchus has emerged as a viable non-human primate model to study various human diseases because of its distinct features and close physiologic, genetic and metabolic similarities to humans. C. jacchus embryonic stem cells (cjESC) and recently generated cjESC-derived hepatocyte-like cells (cjESC-HLCs) could fill the gaps in disease modeling, liver regeneration and metabolic studies. They are extremely useful for cell therapy to regenerate and repair damaged liver tissues in vivo as they could efficiently engraft into the liver parenchyma. For in vitro studies, they would be advantageous for drug design and metabolism in developing novel drugs and cell-based therapies. Specifically, they express both phase I and II metabolic enzymes that share similar substrate specificities, inhibition and induction characteristics, and drug metabolism as their human counterparts. In addition, cjESCs and cjESC-HLCs are advantageous for investigations on emerging research areas, including blastocyst complementation to generate entire livers, and bioengineering of discarded livers to regenerate whole livers for transplantation.

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Arylamine N-Acetyltransferases

Boukouvala,

Fakis,

Stavrakaki

et al. 2024

Reference Module in Biomedical Sciences

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Genetic variants of N-acetyltransferases 1 and 2 (NAT1 and NAT2) in cynomolgus and rhesus macaques

Cited by 7 publications

References 27 publications

Molecular and Functional Characterization of N-Acetyltransferases in Common Marmosets and Pigs

Molecular and Functional Characterization of N-Acetyltransferases in Common Marmosets and Pigs

Utility of Common Marmoset (Callithrix jacchus) Embryonic Stem Cells in Liver Disease Modeling, Tissue Engineering and Drug Metabolism

Arylamine N-Acetyltransferases

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