Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCCNQ3H)

• DOT Name: Arylamine N-acetyltransferase 1 (NAT1)
• Synonyms: EC 2.3.1.5; Arylamide acetylase 1; Monomorphic arylamine N-acetyltransferase; MNAT; N-acetyltransferase type 1; NAT-1
• Gene Name: NAT1
• UniProt ID: ARY1_HUMAN
• PDB ID: 2IJA; 2PQT
• EC Number: 2.3.1.5
• Pfam ID: PF00797
• Sequence:
  MDIEAYLERIGYKKSRNKLDLETLTDILQHQIRAVPFENLNIHCGDAMDLGLEAIFDQVV
  RRNRGGWCLQVNHLLYWALTTIGFETTMLGGYVYSTPAKKYSTGMIHLLLQVTIDGRNYI
  VDAGFGRSYQMWQPLELISGKDQPQVPCVFRLTEENGFWYLDQIRREQYIPNEEFLHSDL
  LEDSKYRKIYSFTLKPRTIEDFESMNTYLQTSPSSVFTSKSFCSLQTPDGVHCLVGFTLT
  HRRFNYKDNTDLIEFKTLSEEEIEKVLKNIFNISLQRKLVPKHGDRFFTI
• 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 Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cotinine	DMCEZ1B	Approved	Arylamine N-acetyltransferase 1 (NAT1) affects the abundance of Cotinine.	[23]

This DOT Affected the Biotransformations of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ammonia	DMOEVK6	Approved	Arylamine N-acetyltransferase 1 (NAT1) increases the acetylation of Ammonia.	[24]
Procainamide	DMNMXR8	Approved	Arylamine N-acetyltransferase 1 (NAT1) increases the acetylation of Procainamide.	[7]
Aminosalicylic acid	DMENSL5	Approved	Arylamine N-acetyltransferase 1 (NAT1) increases the acetylation of Aminosalicylic acid.	[25]
Aminohippuric acid	DMUN54G	Investigative	Arylamine N-acetyltransferase 1 (NAT1) increases the acetylation of Aminohippuric acid.	[24]
Aniline	DMLCAR9	Investigative	Arylamine N-acetyltransferase 1 (NAT1) increases the acetylation of Aniline.	[25]
Asacolitin	DM3WVPJ	Investigative	Arylamine N-acetyltransferase 1 (NAT1) increases the acetylation of Asacolitin.	[25]
Aminobenzoic acid	DMNGW2M	Investigative	Arylamine N-acetyltransferase 1 (NAT1) increases the acetylation of Aminobenzoic acid.	[28]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitrobenzanthrone	DMN6L70	Investigative	Arylamine N-acetyltransferase 1 (NAT1) increases the activity of Nitrobenzanthrone.	[26]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	Arylamine N-acetyltransferase 1 (NAT1) increases the response to substance of 1,6-hexamethylene diisocyanate.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Arylamine N-acetyltransferase 1 (NAT1).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Arylamine N-acetyltransferase 1 (NAT1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the activity of Arylamine N-acetyltransferase 1 (NAT1).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[5]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the activity of Arylamine N-acetyltransferase 1 (NAT1).	[7]
Folic acid	DMEMBJC	Approved	Folic acid decreases the activity of Arylamine N-acetyltransferase 1 (NAT1).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[8]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the activity of Arylamine N-acetyltransferase 1 (NAT1).	[9]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[12]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[17]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[18]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[14]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[19]
Wogonin	DMGCF51	Investigative	Wogonin decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[20]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the activity of Arylamine N-acetyltransferase 1 (NAT1).	[21]
Aloe-emodin	DMPTY8S	Investigative	Aloe-emodin decreases the expression of Arylamine N-acetyltransferase 1 (NAT1).	[22]
Iodoacetamide	DMM4XVL	Investigative	Iodoacetamide decreases the activity of Arylamine N-acetyltransferase 1 (NAT1).	[21]
Dihydrofolic Acid	DM1BDM8	Investigative	Dihydrofolic Acid decreases the activity of Arylamine N-acetyltransferase 1 (NAT1).	[7]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetyl Coa	DMH65Q8	Investigative	Acetyl Coa affects the binding of Arylamine N-acetyltransferase 1 (NAT1).	[21]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [4] 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.
• [5] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [6] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [7] Over-expression, purification, and characterization of recombinant human arylamine N-acetyltransferase 1. Protein J. 2005 Feb;24(2):65-77.
• [8] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [9] Paclitaxel inhibits N-acetyltransferase activity and gene expression in human stomach tumor cells (SC-M1). Res Commun Mol Pathol Pharmacol. 2004;115-116:21-38.
• [10] Sulindac inhibited gene expression and activity of arylamine N-acetyltransferase and DNA-2-aminofluorene adduct formation in T24 human bladder tumor cells. Urol Res. 2001 Dec;29(6):406-11.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] N-acetyltransferase is involved in baicalein-induced N-acetylation of 2-aminofluorene and DNA-2-aminofluorene adduct formation in human leukemia HL-60 cells. In Vivo. 2005 Mar-Apr;19(2):399-405.
• [14] Development of in vitro 3D cell model from hepatocellular carcinoma (HepG2) cell line and its application for genotoxicity testing. Arch Toxicol. 2019 Nov;93(11):3321-3333. doi: 10.1007/s00204-019-02576-6. Epub 2019 Sep 21.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [19] 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.
• [20] Wogonin inhibits N-acetyltransferase activity and gene expression in human leukemia HL-60 cells. Anticancer Res. 2005 Jan-Feb;25(1A):127-32.
• [21] Cyanamide-mediated inhibition of N-acetyltransferase 1. Toxicology. 2012 Dec 8;302(1):1-10.
• [22] Effect of inhibition of aloe-emodin on N-acetyltransferase activity and gene expression in human malignant melanoma cells (A375.S2). Melanoma Res. 2005 Dec;15(6):489-94.
• [23] N-acetyltransferase 1 polymorphism increases cotinine levels in Caucasian children exposed to secondhand smoke: the CCAAPS birth cohort. Pharmacogenomics J. 2015 Apr;15(2):189-95. doi: 10.1038/tpj.2014.44. Epub 2014 Aug 26.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. Pharmacogenetics. 2002 Apr;12(3):227-33. doi: 10.1097/00008571-200204000-00007.
• [28] N-Acetyltransferases, sulfotransferases and heterocyclic amine activation in the breast. Pharmacogenetics. 2001 Jul;11(5):373-88. doi: 10.1097/00008571-200107000-00002.