Arylamine N‐acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery

Abstract

Arylamine N-acetyltransferases (NATs) are polymorphic drug-metabolizing enzymes, acetylating arylamine carcinogens and drugs including hydralazine and sulphonamides. The slow NAT phenotype increases susceptibility to hydralazine and isoniazid toxicity and to occupational bladder cancer. The two polymorphic human NAT loci show linkage disequilibrium. All mammalian Nat genes have an intronless open reading frame and non-coding exons. The human gene products NAT1 and NAT2 have distinct substrate specificities: NAT2 acetylates hydralazine and human NAT1 acetylates p-aminosalicylate (p-AS) and the folate catabolite para-aminobenzoylglutamate (p-abaglu). Human NAT2 is mainly in liver and gut. Human NAT1 and its murine homologue are in many adult tissues and in early embryos. Human NAT1 is strongly expressed in oestrogen receptor-positive breast cancer and may contribute to folate and acetyl CoA homeostasis. NAT enzymes act through a catalytic triad of Cys, His and Asp with the architecture of the active site-modulating specificity. Polymorphisms may cause unfolded protein. The C-terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues. NAT in Salmonella typhimurium supports carcinogen activation and NAT in mycobacteria metabolizes isoniazid with polymorphism a minor factor in isoniazid resistance. Importantly, nat is in a gene cluster essential for Mycobacterium tuberculosis survival inside macrophages. NAT inhibitors are a starting point for novel anti-tuberculosis drugs. Human NAT1-specific inhibitors may act in biomarker detection in breast cancer and in cancer therapy. NAT inhibitors for co-administration with 5-aminosalicylate (5-AS) in inflammatory bowel disease has prompted ongoing investigations of azoreductases in gut bacteria which release 5-AS from prodrugs including balsalazide.

Whole exome sequencing detects variants of genes that mediate response to anticancer drugs

“…Of the genes responsible for the metabolism and transport of anticancer drugs using the WES data, we focused on the genes encoding cytochrome P450 isoforms (CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6) (Bell et al, 2015;Chen and Goldstein, 2009;Crews et al, 2012;Jin et al, 2005;Kim et al, 2004;Kiyotani et al, 2013;Takimoto et al, 2013;Tamaki et al, 2011;Xie et al, 2003), thiopurine methyltransferase (TPMT) (Chouchana et al, 2014), N-acetyltransferase 2 (NAT2) (Sim et al, 2014), UDP glucuronosyl transferase family 1 member A1 (UGT1A1) (Cheng et al, 2014;Sugatani, 2013), catechol-O-methyltransferase (COMT) (Zubieta et al, 2003), ATP-binding cassette subfamily B member 1 (ABCB1) (Bell et al, 2015;Frederiks et al, 2015), and cytidine deaminase (CDA) (Sugiyama et al, 2007(Sugiyama et al, , 2009, in the present study (Table 2) because the variants of these genes were previously described to affect drug response in Japanese populations (Kurose et al, 2012).…”

Effect of acetaminophen on sulfamethazine acetylation in male volunteers

“…11 NAT2 genotypes confer their respective acetylation phenotype as slow, intermediate or rapid, resulting in their specific metabolic rate, therapeutic response, and susceptibility to drug toxicity. 12,13 NAT1 is located in almost every tissue examined, 14 whereas NAT2 is mainly expressed in the liver 3 and gut. 15 The irreversible inhibition and inactivation of biotransformation enzymes like NATs by xenobiotics and their metabolites is of toxicological and clinical significance.…”

“…2 N-acetyltransferase 2 (NAT2) (EC 2.3.1.5) is an N-acetylation mediated drug-metabolizing polymorphic enzyme, acts on arylamine carcinogens and drugs including hydralazine and sulfonamide. 3 NAT2 contributes significantly in individual's susceptibility for drugs regarding efficacy and side effects. 4 NAT2 also plays a significant role in detoxification, neutralization of potential carcinogens, and altering the susceptibility to cancer majorly through acetylation.…”

<em>In Silico</em> Screening and Analysis of Potential Inhibitors of Arylamine N-Acetyltransferases (NATs) from the Traditional Chinese Medicine: A Study Using Free Available Tools

“…These enzymes play an important role in the detoxification and metabolic activation of xenobiotics [4,7,8] as well as in the synthesis of endogenous compounds [9,10]. potential biomarkers as well as potential drugs for cancer treatment [12][13][14][15]. In another therapeutic perspective, studies showed that NAT gene of Mycobacterium tuberculosis (M. tuberculosis) is part of a cluster essential for the survival of the mycobacteria in the environment inside macrophage [10,16,17].…”