Detail Information of Exogenous Modulation

General Information of Drug Transporter (DT)
DT ID DTD0345 Transporter Info
Gene Name SLC39A4
Transporter Name Zinc transporter ZIP4
Gene ID
55630
UniProt ID
Q6P5W5
Exogenous factors (drugs, dietary constituents, etc.) Modulation of This DT (EGM)

Chemical Compound

  DT Modulation1

 Cyclosporine results in decreased methylation of SLC39A4 promoter [24]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation1

 Valproic Acid results in increased methylation of SLC39A4 gene [6]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation1

 Ammonium Chloride inhibits the reaction Zinc results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation2

 benzyloxycarbonylleucyl-leucyl-leucine aldehyde inhibits the reaction Zinc results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation3

 methyl-beta-cyclodextrin inhibits the reaction Zinc results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation4

 SLC39A4 protein results in increased transport of Zinc [29]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation5

 SLC39A4 protein results in increased uptake of Zinc [17]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation6

 Sucrose inhibits the reaction Zinc results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation7

 Zinc affects the expression of SLC39A4 protein [30]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation8

 Zinc results in increased ubiquitination of and results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation1

 Benzo(a)pyrene affects the methylation of SLC39A4 promoter [20]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation2

 Benzo(a)pyrene results in increased methylation of SLC39A4 exon [20]

Regulation Mechanism

 Transcription Factor Info

  Ammonium Chloride

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Ammonium Chloride inhibits the reaction Zinc results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  aristolochic acid I

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 aristolochic acid I results in decreased expression of SLC39A4 mRNA [18]

Regulation Mechanism

 Transcription Factor Info

  benzyloxycarbonylleucyl-leucyl-leucine aldehyde

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 benzyloxycarbonylleucyl-leucyl-leucine aldehyde inhibits the reaction Zinc results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  beta-lapachone

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 beta-lapachone results in increased expression of SLC39A4 mRNA [21]

Regulation Mechanism

 Transcription Factor Info

  beta-Naphthoflavone

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 beta-Naphthoflavone results in decreased expression of SLC39A4 protein [22]

Regulation Mechanism

 Transcription Factor Info

  bisphenol A

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 bisphenol A affects the expression of SLC39A4 mRNA [15]

Regulation Mechanism

 Transcription Factor Info

  cobaltous chloride

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 cobaltous chloride results in decreased expression of SLC39A4 mRNA [23]

Regulation Mechanism

 Transcription Factor Info

  deoxynivalenol

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 deoxynivalenol results in decreased expression of SLC39A4 protein [22]

Regulation Mechanism

 Transcription Factor Info

  Dichlorodiphenyl Dichloroethylene

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Dichlorodiphenyl Dichloroethylene results in increased expression of SLC39A4 mRNA [25]

Regulation Mechanism

 Transcription Factor Info

  epigallocatechin gallate

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 epigallocatechin gallate results in increased expression of SLC39A4 mRNA [3]

Regulation Mechanism

 Transcription Factor Info

  licochalcone B

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 licochalcone B results in increased expression of SLC39A4 mRNA [26]

Regulation Mechanism

 Transcription Factor Info

  methyl-beta-cyclodextrin

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 methyl-beta-cyclodextrin inhibits the reaction Zinc results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  Methyl Methanesulfonate

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Methyl Methanesulfonate results in decreased expression of SLC39A4 mRNA [13]

Regulation Mechanism

 Transcription Factor Info

  N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine results in increased expression of SLC39A4 mRNA [27]

Regulation Mechanism

 Transcription Factor Info

  Okadaic Acid

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Okadaic Acid results in increased expression of SLC39A4 mRNA [28]

Regulation Mechanism

 Transcription Factor Info

  potassium perchlorate

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 potassium perchlorate results in decreased expression of SLC39A4 mRNA [7]

Regulation Mechanism

 Transcription Factor Info

  sodium arsenite

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 sodium arsenite results in decreased expression of SLC39A4 mRNA [25]

Regulation Mechanism

 Transcription Factor Info

  Sucrose

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Sucrose inhibits the reaction Zinc results in increased degradation of SLC39A4 protein [17]

Regulation Mechanism

 Transcription Factor Info

  Tetrachlorodibenzodioxin

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Tetrachlorodibenzodioxin results in increased expression of SLC39A4 mRNA [11]

Regulation Mechanism

 Transcription Factor Info

  Thiram

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Thiram results in decreased expression of SLC39A4 mRNA [25]

Regulation Mechanism

 Transcription Factor Info

  zinc chloride

            2 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 zinc chloride inhibits the reaction Grape Seed Proanthocyanidins results in increased expression of SLC39A4 mRNA [3]

Regulation Mechanism

 Transcription Factor Info

  DT Modulation2

 zinc chloride results in decreased expression of SLC39A4 mRNA [3]

Regulation Mechanism

 Transcription Factor Info

Approved Drug

  Hydrogen Peroxide

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Hydrogen Peroxide affects the expression of SLC39A4 [1]

  Calcitriol

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Calcitriol inhibits the expression of SLC39A4 [2]

  Cisplatin

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Cisplatin increases the expression of SLC39A4 [4]

  Cyclosporine

            2 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Cyclosporine inhibits the expression of SLC39A4 [5]

  Valproic Acid

            2 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Valproic Acid inhibits the expression of SLC39A4 [6]

  Potassium perchlorate

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Potassium perchlorate inhibits the expression of SLC39A4 [7]

Drug Marketed but not Approved by US FDA

  Zinc chloride

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Zinc chloride inhibits the expression of SLC39A4 [3]

  Rotenone

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Rotenone increases the expression of SLC39A4 [8]

Drug in Phase 2 Trial

  Bisphenol A

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Bisphenol A affects the expression of SLC39A4 [15]

Drug in Phase 1 Trial

  Quercetin

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Quercetin increases the expression of SLC39A4 [12]

Investigative Drug

  Coumestrol

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Coumestrol increases the expression of SLC39A4 [10]

Patented Pharmaceutical Agent

  GSK-J4

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 GSK-J4 inhibits the expression of SLC39A4 [14]

Natural Product

  Epigallocatechin gallate

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 (-)-Epigallocatechin-3-O-gallate induces the activity of SLC39A4 [16]

Plant Extract

  Grape Seed Proanthocyanidins

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Grape Seed Proanthocyanidins increases the expression of SLC39A4 [3]

Environmental toxicant

  Zinc

            9 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Zinc inhibits the expression of SLC39A4 [9]

Regulation Mechanism

 via the inhibition of Krueppel-like factor 4 (KLF4) Transcription Factor Info

Cell System

 CD-1 mice

  Polychlorinated dibenzodioxin

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Polychlorinated dibenzodioxin increases the expression of SLC39A4 [12]

Acute Toxic Substance

  Formaldehyde

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Formaldehyde inhibits the expression of SLC39A4 [13]

Carcinogen

  Benzo(a)pyrene

            3 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Benzo(a)pyrene increases the expression of SLC39A4 [11]

  Ethyl Methanesulfonate

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Ethyl Methanesulfonate inhibits the expression of SLC39A4 [13]

  Arsenic

            1 DT Activity Modulations Related to This Exogenous Factor Click to Show/Hide the Full List

  DT Modulation1

 Arsenic affects the methylation of SLC39A4 gene [19]

Regulation Mechanism

 Transcription Factor Info
References
1 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.
2 Cellular zinc homeostasis is a regulator in monocyte differentiation of HL-60 cells by 1 alpha,25-dihydroxyvitamin D3. J Leukoc Biol. 2010 May;87(5):833-44.
3 Dietary catechins and procyanidins modulate zinc homeostasis in human HepG2 cells. J Nutr Biochem. 2011 Feb;22(2):153-63.
4 Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
5 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
6 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.
7 Changes in trophoblasts gene expression in response to perchlorate exposition. Toxicol In Vitro. 2018 Aug;50:328-335.
8 Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone. Arch Toxicol. 2018 Aug;92(8):2587-2606.
9 Krupel-like factor 4 regulates adaptive expression of the zinc transporter Zip4 in mouse small intestine. Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G517-23.
10 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
11 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.
12 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.
13 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
14 Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells. J Biol Chem. 2018 Feb 16;293(7):2422-2437.
15 Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134.
16 Attenuation of progressive hearing loss in DBA/2J mice by reagents that affect epigenetic modifications is associated with up-regulation of the zinc importer Zip4. PLoS One. 2015 Apr 14;10(4):e0124301.
17 A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity. J Biol Chem. 2007;282(10):6992-7000.
18 Integration of transcriptomic, proteomic and metabolomic data to reveal the biological mechanisms of AAI injury in renal epithelial cells. Toxicol In Vitro. 2021;70:105054.
19 Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106.
20 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017;8(1):1369-1391.
21 Lapachone induces ferroptosis of colorectal cancer cells via NCOA4-mediated ferritinophagy by activating JNK pathway. Chem Biol Interact. 2024;389:110866.
22 Alterations in the proteomes of HepG2 and IHKE cells inflicted by six selected mycotoxins. Arch Toxicol. 2025;99(2):701-715.
23 Alterations of histone modifications by cobalt compounds. Carcinogenesis. 2009;30(7):1243-51.
24 Integrative "-Omics" Analysis in Primary Human Hepatocytes Unravels Persistent Mechanisms of Cyclosporine A-Induced Cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
25 High-Throughput Transcriptomics of Nontumorigenic Breast Cells Exposed to Environmentally Relevant Chemicals. Environ Health Perspect. 2024;132(4):47002.
26 Integrated miRNA and mRNA omics reveal the anti-cancerous mechanism of Licochalcone B on Human Hepatoma Cell HepG2. Food Chem Toxicol. 2021;150:112096.
27 Cooperation of metallothionein and zinc transporters for regulating zinc homeostasis in human intestinal Caco-2 cells. Nutr Res. 2008;28(6):406-13.
28 A multi-omics approach to elucidate okadaic acid-induced changes in human HepaRG hepatocarcinoma cells. Arch Toxicol. 2024;98(9):2919-2935.
29 Expression of ZnT and ZIP zinc transporters in the human RPE and their regulation by neurotrophic factors. Invest Ophthalmol Vis Sci. 2008;49(3):1221-31.
30 Effects of zinc exposure on zinc transporter expression in human intestinal cells of varying maturity. J Pediatr Gastroenterol Nutr. 2010 Jun;50(6):587-95.

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