Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZT0LKT)

• DOT Name: ATP-binding cassette sub-family C member 6 (ABCC6)
• Synonyms: EC 7.6.2.-; EC 7.6.2.3; Anthracycline resistance-associated protein; Multi-specific organic anion transporter E; MOAT-E; Multidrug resistance-associated protein 6
• Gene Name: ABCC6
• Related Disease:
  Arterial calcification, generalized, of infancy, 2
  Autosomal recessive inherited pseudoxanthoma elasticum
  Arterial calcification
• UniProt ID: MRP6_HUMAN
• PDB ID: 6BZR; 6BZS; 6NLO; 6P7F
• EC Number: 7.6.2.-; 7.6.2.3
• Pfam ID: PF00664 ; PF00005
• Sequence:
  MAAPAEPCAGQGVWNQTEPEPAATSLLSLCFLRTAGVWVPPMYLWVLGPIYLLFIHHHGR
  GYLRMSPLFKAKMVLGFALIVLCTSSVAVALWKIQQGTPEAPEFLIHPTVWLTTMSFAVF
  LIHTERKKGVQSSGVLFGYWLLCFVLPATNAAQQASGAGFQSDPVRHLSTYLCLSLVVAQ
  FVLSCLADQPPFFPEDPQQSNPCPETGAAFPSKATFWWVSGLVWRGYRRPLRPKDLWSLG
  RENSSEELVSRLEKEWMRNRSAARRHNKAIAFKRKGGSGMKAPETEPFLRQEGSQWRPLL
  KAIWQVFHSTFLLGTLSLIISDVFRFTVPKLLSLFLEFIGDPKPPAWKGYLLAVLMFLSA
  CLQTLFEQQNMYRLKVLQMRLRSAITGLVYRKVLALSSGSRKASAVGDVVNLVSVDVQRL
  TESVLYLNGLWLPLVWIVVCFVYLWQLLGPSALTAIAVFLSLLPLNFFISKKRNHHQEEQ
  MRQKDSRARLTSSILRNSKTIKFHGWEGAFLDRVLGIRGQELGALRTSGLLFSVSLVSFQ
  VSTFLVALVVFAVHTLVAENAMNAEKAFVTLTVLNILNKAQAFLPFSIHSLVQARVSFDR
  LVTFLCLEEVDPGVVDSSSSGSAAGKDCITIHSATFAWSQESPPCLHRINLTVPQGCLLA
  VVGPVGAGKSSLLSALLGELSKVEGFVSIEGAVAYVPQEAWVQNTSVVENVCFGQELDPP
  WLERVLEACALQPDVDSFPEGIHTSIGEQGMNLSGGQKQRLSLARAVYRKAAVYLLDDPL
  AALDAHVGQHVFNQVIGPGGLLQGTTRILVTHALHILPQADWIIVLANGAIAEMGSYQEL
  LQRKGALMCLLDQARQPGDRGEGETEPGTSTKDPRGTSAGRRPELRRERSIKSVPEKDRT
  TSEAQTEVPLDDPDRAGWPAGKDSIQYGRVKATVHLAYLRAVGTPLCLYALFLFLCQQVA
  SFCRGYWLSLWADDPAVGGQQTQAALRGGIFGLLGCLQAIGLFASMAAVLLGGARASRLL
  FQRLLWDVVRSPISFFERTPIGHLLNRFSKETDTVDVDIPDKLRSLLMYAFGLLEVSLVV
  AVATPLATVAILPLFLLYAGFQSLYVVSSCQLRRLESASYSSVCSHMAETFQGSTVVRAF
  RTQAPFVAQNNARVDESQRISFPRLVADRWLAANVELLGNGLVFAAATCAVLSKAHLSAG
  LVGFSVSAALQVTQTLQWVVRNWTDLENSIVSVERMQDYAWTPKEAPWRLPTCAAQPPWP
  QGGQIEFRDFGLRYRPELPLAVQGVSFKIHAGEKVGIVGRTGAGKSSLASGLLRLQEAAE
  GGIWIDGVPIAHVGLHTLRSRISIIPQDPILFPGSLRMNLDLLQEHSDEAIWAALETVQL
  KALVASLPGQLQYKCADRGEDLSVGQKQLLCLARALLRKTQILILDEATAAVDPGTELQM
  QAMLGSWFAQCTVLLIAHRLRSVMDCARVLVMDKGQVAESGSPAQLLAQKGLFYRLAQES
  GLV
• Function: [Isoform 1]: ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Mediates ATP-dependent transport of glutathione conjugates such as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS) (in vitro), and an anionic cyclopentapeptide endothelin antagonist, BQ-123. May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Does not appear to actively transport drugs outside the cell. Confers low levels of cellular resistance to etoposide, teniposide, anthracyclines and cisplatin ; [Isoform 1]: Mediates the release of nucleoside triphosphates, predominantly ATP, into the circulation, where it is rapidly converted into AMP and the mineralization inhibitor inorganic pyrophosphate (PPi) by the ecto-enzyme ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), therefore playing a role in PPi homeostasis; [Isoform 2]: Inhibits TNF-alpha-mediated apoptosis through blocking one or more caspases.
• Tissue Specificity: Expressed in kidney and liver. Very low expression in other tissues. In testis, localized to peritubular myoid cells, Leydig cells, along the basal membrane of Sertoli cells and moderately in the adluminal compartment of the seminiferous tubules .
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway:
  Defective ABCC6 causes PXE (R-HSA-5690338)
  ABC-family proteins mediated transport (R-HSA-382556)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arterial calcification, generalized, of infancy, 2	DIS7257O	Definitive	Autosomal recessive	[1]
Autosomal recessive inherited pseudoxanthoma elasticum	DISV7IU5	Definitive	Autosomal recessive	[2]
Arterial calcification	DIS9BJ1Y	Supportive	Autosomal dominant	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Docetaxel	DMDI269	Approved	ATP-binding cassette sub-family C member 6 (ABCC6) affects the response to substance of Docetaxel.	[26]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
LTC4	DM702WR	Investigative	ATP-binding cassette sub-family C member 6 (ABCC6) affects the transport of LTC4.	[20]

27 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 ATP-binding cassette sub-family C member 6 (ABCC6).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[15]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of ATP-binding cassette sub-family C member 6 (ABCC6).	[16]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[17]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[18]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[6]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[19]
Benzbromarone	DMC3YUA	Approved	Benzbromarone decreases the activity of ATP-binding cassette sub-family C member 6 (ABCC6).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[21]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the activity of ATP-binding cassette sub-family C member 6 (ABCC6).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ATP-binding cassette sub-family C member 6 (ABCC6).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate affects the binding of ATP-binding cassette sub-family C member 6 (ABCC6).	[20]

References

• [1] Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012 Jan 13;90(1):25-39. doi: 10.1016/j.ajhg.2011.11.020. Epub 2011 Dec 29.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Generalized Arterial Calcification of Infancy. 2014 Nov 13 [updated 2020 Dec 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] 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.
• [5] 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.
• [6] Expression of the human ABCC6 gene is induced by retinoids through the retinoid X receptor. Biochem Biophys Res Commun. 2006 Dec 1;350(4):1082-7. doi: 10.1016/j.bbrc.2006.10.007. Epub 2006 Oct 10.
• [7] 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.
• [8] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab Dispos. 2006 Oct;34(10):1756-63. doi: 10.1124/dmd.106.010033. Epub 2006 Jul 12.
• [13] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [14] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [15] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [16] Multidrug resistance protein-6 (MRP6) in human dermal fibroblasts. Comparison between cells from normal subjects and from Pseudoxanthoma elasticum patients. Matrix Biol. 2003 Nov;22(6):491-500. doi: 10.1016/j.matbio.2003.09.001.
• [17] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [18] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [19] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [20] Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem. 2002 May 10;277(19):16860-7.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [23] 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.
• [24] 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. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [25] 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.
• [26] Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. OMICS. 2013 Jul;17(7):353-67. doi: 10.1089/omi.2013.0019. Epub 2013 Jun 11.