Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGFK4MH)

• DOT Name: Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1)
• Synonyms: NHERF-3; CFTR-associated protein of 70 kDa; Na(+)/H(+) exchanger regulatory factor 3; Na/Pi cotransporter C-terminal-associated protein 1; NaPi-Cap1; PDZ domain-containing protein 1; Sodium-hydrogen exchanger regulatory factor 3
• Gene Name: PDZK1
• UniProt ID: NHRF3_HUMAN
• PDB ID: 2EEI; 2EEJ; 2VSP; 3TMH; 4Q2P; 6EZI
• Pfam ID: PF00595
• Sequence:
  MTSTFNPRECKLSKQEGQNYGFFLRIEKDTEGHLVRVVEKCSPAEKAGLQDGDRVLRING
  VFVDKEEHMQVVDLVRKSGNSVTLLVLDGDSYEKAVKTRVDLKELGQSQKEQGLSDNILS
  PVMNGGVQTWTQPRLCYLVKEGGSYGFSLKTVQGKKGVYMTDITPQGVAMRAGVLADDHL
  IEVNGENVEDASHEEVVEKVKKSGSRVMFLLVDKETDKRHVEQKIQFKRETASLKLLPHQ
  PRIVEMKKGSNGYGFYLRAGSEQKGQIIKDIDSGSPAEEAGLKNNDLVVAVNGESVETLD
  HDSVVEMIRKGGDQTSLLVVDKETDNMYRLAHFSPFLYYQSQELPNGSVKEAPAPTPTSL
  EVSSPPDTTEEVDHKPKLCRLAKGENGYGFHLNAIRGLPGSFIKEVQKGGPADLAGLEDE
  DVIIEVNGVNVLDEPYEKVVDRIQSSGKNVTLLVCGKKAYDYFQAKKIPIVSSLADPLDT
  PPDSKEGIVVESNHDSHMAKERAHSTASHSSSNSEDTEM
• Function: A scaffold protein that connects plasma membrane proteins and regulatory components, regulating their surface expression in epithelial cells apical domains. May be involved in the coordination of a diverse range of regulatory processes for ion transport and second messenger cascades. In complex with NHERF1, may cluster proteins that are functionally dependent in a mutual fashion and modulate the trafficking and the activity of the associated membrane proteins. May play a role in the cellular mechanisms associated with multidrug resistance through its interaction with ABCC2 and PDZK1IP1. May potentiate the CFTR chloride channel activity. Required for normal cell-surface expression of SCARB1. Plays a role in maintaining normal plasma cholesterol levels via its effects on SCARB1. Plays a role in the normal localization and function of the chloride-anion exchanger SLC26A6 to the plasma membrane in the brush border of the proximal tubule of the kidney. May be involved in the regulation of proximal tubular Na(+)-dependent inorganic phosphate cotransport therefore playing an important role in tubule function.
• Tissue Specificity: Expression is limited to epithelial cells. Expressed in the kidney (brush border of proximal tubule), pancreas, liver, and small intestine. Expressed at a lower level in the adrenal cortex, testis and stomach. Overexpressed in breast, renal and lung carcinomas.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[4]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[4]
Estrone	DM5T6US	Approved	Estrone increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[10]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[8]
Estriol	DMOEM2I	Approved	Estriol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[4]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[12]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[15]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[18]
Daidzein	DMRFTJX	Investigative	Daidzein increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[12]
N-nonylphenol	DMH3OUX	Investigative	N-nonylphenol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF3 (PDZK1).	[4]

References

• [1] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1. Mol Endocrinol. 2004 Feb;18(2):402-11. doi: 10.1210/me.2003-0202. Epub 2003 Nov 6.
• [5] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [7] 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.
• [8] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals. Environ Health Perspect. 2004 May;112(7):773-81. doi: 10.1289/ehp.6753.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Expression profiling of the estrogen responsive genes in response to phytoestrogens using a customized DNA microarray. FEBS Lett. 2005 Mar 14;579(7):1732-40.
• [13] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [14] Gene expression profiling in Caco-2 human colon cells exposed to TCDD, benzo[a]pyrene, and natural Ah receptor agonists from cruciferous vegetables and citrus fruits. Toxicol In Vitro. 2008 Mar;22(2):396-410.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.