Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBPDQOY)

• DOT Name: Arylamine N-acetyltransferase 2 (NAT2)
• Synonyms: EC 2.3.1.5; Arylamide acetylase 2; N-acetyltransferase type 2; NAT-2; Polymorphic arylamine N-acetyltransferase; PNAT
• Gene Name: NAT2
• UniProt ID: ARY2_HUMAN
• PDB ID: 2PFR
• EC Number: 2.3.1.5
• Pfam ID: PF00797
• Sequence:
  MDIEAYFERIGYKNSRNKLDLETLTDILEHQIRAVPFENLNMHCGQAMELGLEAIFDHIV
  RRNRGGWCLQVNQLLYWALTTIGFQTTMLGGYFYIPPVNKYSTGMVHLLLQVTIDGRNYI
  VDAGSGSSSQMWQPLELISGKDQPQVPCIFCLTEERGIWYLDQIRREQYITNKEFLNSHL
  LPKKKHQKIYLFTLEPRTIEDFESMNTYLQTSPTSSFITTSFCSLQTPEGVYCLVGFILT
  YRKFNYKDNTDLVEFKTLTEEEVEEVLRNIFKISLGRNLVPKPGDGSLTI
• Function: Participates in the detoxification of a plethora of hydrazine and arylamine drugs. Catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivate several known carcinogens.
• KEGG Pathway:
  Caffeine metabolism (hsa00232)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Chemical carcinogenesis - D. adducts (hsa05204)
• Reactome Pathway:
  Paracetamol ADME (R-HSA-9753281)
  Acetylation (R-HSA-156582)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Arylamine N-acetyltransferase 2 (NAT2) affects the response to substance of Aspirin.	[16]
Ibuprofen	DM8VCBE	Approved	Arylamine N-acetyltransferase 2 (NAT2) increases the Drug resistance ADR of Ibuprofen.	[17]
Ammonia	DMOEVK6	Approved	Arylamine N-acetyltransferase 2 (NAT2) decreases the activity of Ammonia.	[21]
Nitrobenzanthrone	DMN6L70	Investigative	Arylamine N-acetyltransferase 2 (NAT2) increases the activity of Nitrobenzanthrone.	[31]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	Arylamine N-acetyltransferase 2 (NAT2) increases the response to substance of 1,6-hexamethylene diisocyanate.	[33]

This DOT Affected the Biotransformations of 14 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Isoniazid	DM5JVS3	Approved	Arylamine N-acetyltransferase 2 (NAT2) decreases the acetylation of Isoniazid.	[18]
Sulfasalazine	DMICA9H	Approved	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Sulfasalazine.	[19]
Hydralazine	DMU8JGH	Approved	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Hydralazine.	[20]
Procainamide	DMNMXR8	Approved	Arylamine N-acetyltransferase 2 (NAT2) affects the acetylation of Procainamide.	[23]
Sulfadiazine	DMTW3R8	Approved	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Sulfadiazine.	[24]
Dapsone	DM4LT8A	Approved	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Dapsone.	[25]
Sulfapyridine	DMIUYFH	Approved	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Sulfapyridine.	[27]
Sulfamethazine	DMRGZ16	Approved	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Sulfamethazine.	[29]
PMID28870136-Compound-52	DMFDERP	Patented	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of PMID28870136-Compound-52.	[30]
Aminohippuric acid	DMUN54G	Investigative	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Aminohippuric acid.	[32]
Methylenedioxymethamphetamine	DMYVU47	Investigative	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Methylenedioxymethamphetamine.	[34]
Aniline	DMLCAR9	Investigative	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Aniline.	[20]
Asacolitin	DM3WVPJ	Investigative	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Asacolitin.	[20]
Phenethylamine	DMX0G4F	Investigative	Arylamine N-acetyltransferase 2 (NAT2) increases the acetylation of Phenethylamine.	[34]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dextromethorphan	DMUDJZM	Approved	Arylamine N-acetyltransferase 2 (NAT2) affects the metabolism of Dextromethorphan.	[22]
Sulfamethoxazole	DMB08GE	Approved	Arylamine N-acetyltransferase 2 (NAT2) increases the metabolism of Sulfamethoxazole.	[26]
Chlorzoxazone	DMCYVDT	Approved	Arylamine N-acetyltransferase 2 (NAT2) affects the metabolism of Chlorzoxazone.	[28]

16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[2]
Quercetin	DM3NC4M	Approved	Quercetin increases the activity of Arylamine N-acetyltransferase 2 (NAT2).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the activity of Arylamine N-acetyltransferase 2 (NAT2).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[8]
Sodium acetate anhydrous	DMH21E0	Approved	Sodium acetate anhydrous increases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[1]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[12]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[9]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[13]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Arylamine N-acetyltransferase 2 (NAT2).	[14]
Iodoacetamide	DMM4XVL	Investigative	Iodoacetamide decreases the activity of Arylamine N-acetyltransferase 2 (NAT2).	[15]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Arylamine N-acetyltransferase 2 (NAT2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Arylamine N-acetyltransferase 2 (NAT2).	[11]

References

• [1] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase and xanthine oxidase activity in healthy volunteers. Clin Exp Pharmacol Physiol. 2009 Aug;36(8):828-33.
• [5] The xenobiotic-metabolizing enzymes arylamine N-acetyltransferases in human lens epithelial cells: inactivation by cellular oxidants and UVB-induced oxidative stress. Mol Pharmacol. 2005 Apr;67(4):1299-306.
• [6] Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol. 2016 Oct;163:77-87.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [9] Transcriptional Regulation of Human Arylamine N-Acetyltransferase 2 Gene by Glucose and Insulin in Liver Cancer Cell Lines. Toxicol Sci. 2022 Nov 23;190(2):158-172. doi: 10.1093/toxsci/kfac103.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Modulation of the xenobiotic transformation system and inflammatory response by ochratoxin A exposure using a co-culture system of Caco-2 and HepG2 cells. Food Chem Toxicol. 2015 Dec;86:245-52.
• [13] Protective effects of xanthohumol against the genotoxicity of heterocyclic aromatic amines MeIQx and PhIP in bacteria and in human hepatoma (HepG2) cells. Food Chem Toxicol. 2012 Mar;50(3-4):949-55.
• [14] Butyrate interacts with benzo[a]pyrene to alter expression and activities of xenobiotic metabolizing enzymes involved in metabolism of carcinogens within colon epithelial cell models. Toxicology. 2019 Jan 15;412:1-11.
• [15] Cyanamide-mediated inhibition of N-acetyltransferase 1. Toxicology. 2012 Dec 8;302(1):1-10.
• [16] Association analysis of N-acetyl transferase-2 polymorphisms with aspirin intolerance among asthmatics. Pharmacogenomics. 2010 Jul;11(7):951-8. doi: 10.2217/pgs.10.65.
• [17] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [18] Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients. J Toxicol Sci. 2008 May;33(2):187-95. doi: 10.2131/jts.33.187.
• [19] Adverse effects of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene. J Rheumatol. 2002 Dec;29(12):2492-9.
• [20] Eukaryotic arylamine N-acetyltransferase. Investigation of substrate specificity by high-throughput screening. Biochem Pharmacol. 2005 Jan 15;69(2):347-59. doi: 10.1016/j.bcp.2004.09.014. Epub 2004 Nov 24.
• [21] Urinary mutagenicity, CYP1A2 and NAT2 activity in textile industry workers. J Occup Health. 2004 Nov;46(6):440-7. doi: 10.1539/joh.46.440.
• [22] Comparison of various urine collection intervals for caffeine and dextromethorphan phenotyping in children. J Clin Pharmacol. 2004 Jul;44(7):708-14. doi: 10.1177/0091270004266624.
• [23] Interindividual variability in 5-Fluorouracil metabolism and procainamide N-acetylation in human liver cytosol. Biol Pharm Bull. 2005 Jun;28(6):1071-4. doi: 10.1248/bpb.28.1071.
• [24] Identification of cytochrome P450 and arylamine N-acetyltransferase isoforms involved in sulfadiazine metabolism. Drug Metab Dispos. 2005 Jul;33(7):969-76.
• [25] N-acetyltransferase 2 acetylation polymorphism: prevalence of slow acetylators does not differ between atopic dermatitis patients and healthy subjects. Skin Pharmacol Appl Skin Physiol. 2003 Nov-Dec;16(6):386-92. doi: 10.1159/000072934.
• [26] Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity. Pharmacogenomics J. 2007 Apr;7(2):144-52. doi: 10.1038/sj.tpj.6500407. Epub 2006 Jul 18.
• [27] Pharmacogenetic characterization of sulfasalazine disposition based on NAT2 and ABCG2 (BCRP) gene polymorphisms in humans. Clin Pharmacol Ther. 2008 Jul;84(1):95-103.
• [28] Effects of cigarette smoking and carbon monoxide on chlorzoxazone and caffeine metabolism. Clin Pharmacol Ther. 2003 Nov;74(5):468-74. doi: 10.1016/j.clpt.2003.07.001.
• [29] Functional genomics of C190T single nucleotide polymorphism in human N-acetyltransferase 2. Biol Chem. 2002 Jun;383(6):983-7. doi: 10.1515/BC.2002.105.
• [30] Re-investigation of the concordance of human NAT2 phenotypes and genotypes. Arch Toxicol. 2005 Apr;79(4):196-200. doi: 10.1007/s00204-004-0622-8. Epub 2004 Nov 19.
• [31] Environmental pollutant and potent mutagen 3-nitrobenzanthrone forms DNA adducts after reduction by NAD(P)H:quinone oxidoreductase and conjugation by acetyltransferases and sulfotransferases in human hepatic cytosols. Cancer Res. 2005 Apr 1;65(7):2644-52. doi: 10.1158/0008-5472.CAN-04-3544.
• [32] GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high-risk population. Int J Cancer. 2004 Jul 1;110(4):598-604. doi: 10.1002/ijc.20157.
• [33] N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. Pharmacogenetics. 2002 Apr;12(3):227-33. doi: 10.1097/00008571-200204000-00007.
• [34] N-acetyltransferase 2 genetic polymorphism modifies genotoxic and oxidative damage from new psychoactive substances. Arch Toxicol. 2023 Jan;97(1):189-199. doi: 10.1007/s00204-022-03383-2. Epub 2022 Sep 23.