Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU9OWOW)

• DOT Name: N-acetyltransferase 8 (NAT8)
• Synonyms: EC 2.3.1.-; Acetyltransferase 2; ATase2; Camello-like protein 1; Cysteinyl-conjugate N-acetyltransferase; CCNAT; EC 2.3.1.80
• Gene Name: NAT8
• UniProt ID: NAT8_HUMAN
• EC Number: 2.3.1.-; 2.3.1.80
• Pfam ID: PF00583
• Sequence:
  MAPCHIRKYQESDRQWVVGLLSRGMAEHAPATFRQLLKLPRTLILLLGGPLALLLVSGSW
  LLALVFSISLFPALWFLAKKPWTEYVDMTLCTDMSDITKSYLSERGSCFWVAESEEKVVG
  MVGALPVDDPTLREKRLQLFHLFVDSEHRRQGIAKALVRTVLQFARDQGYSEVILDTGTI
  QLSAMALYQSMGFKKTGQSFFCVWARLVALHTVHFIYHLPSSKVGSL
• Function: Acetylates the free alpha-amino group of cysteine S-conjugates to form mercapturic acids. This is the final step in a major route for detoxification of a wide variety of reactive electrophiles which starts with their incorporation into glutathione S-conjugates. The glutathione S-conjugates are then further processed into cysteine S-conjugates and finally mercapturic acids which are water soluble and can be readily excreted in urine or bile. Alternatively, may have a lysine N-acetyltransferase activity catalyzing peptidyl-lysine N6-acetylation of various proteins. Thereby, may regulate apoptosis through the acetylation and the regulation of the expression of PROM1. May also regulate amyloid beta-peptide secretion through acetylation of BACE1 and the regulation of its expression in neurons.
• Tissue Specificity: Preferentially expressed in liver and kidney. Also detected in brain (at protein level).
• KEGG Pathway:
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Amyloid fiber formation (R-HSA-977225)
• BioCyc Pathway: MetaCyc:ENSG00000144035-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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 N-acetyltransferase 8 (NAT8).	[1]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of N-acetyltransferase 8 (NAT8).	[13]

13 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 N-acetyltransferase 8 (NAT8).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-acetyltransferase 8 (NAT8).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of N-acetyltransferase 8 (NAT8).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of N-acetyltransferase 8 (NAT8).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of N-acetyltransferase 8 (NAT8).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of N-acetyltransferase 8 (NAT8).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of N-acetyltransferase 8 (NAT8).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of N-acetyltransferase 8 (NAT8).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of N-acetyltransferase 8 (NAT8).	[9]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of N-acetyltransferase 8 (NAT8).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-acetyltransferase 8 (NAT8).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of N-acetyltransferase 8 (NAT8).	[2]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of N-acetyltransferase 8 (NAT8).	[12]

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] 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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol. 2016 Oct;163:77-87.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.