Details of Drug Off-Target (DOT)

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

• DOT Name: ATP-binding cassette sub-family B member 6 (ABCB6)
• Synonyms: ABC-type heme transporter ABCB6; EC 7.6.2.5; Mitochondrial ABC transporter 3; Mt-ABC transporter 3; P-glycoprotein-related protein; Ubiquitously-expressed mammalian ABC half transporter
• Gene Name: ABCB6
• Related Disease:
  Dyschromatosis universalis hereditaria
  Familial pseudohyperkalemia
  Microphthalmia, isolated, with coloboma
  Dyschromatosis universalis hereditaria 3
  Microphthalmia, isolated, with coloboma 7
• UniProt ID: ABCB6_HUMAN
• PDB ID: 3NH6; 3NH9; 3NHA; 3NHB; 7D7N; 7D7R; 7DNY; 7DNZ; 7EKL; 7EKM; 8FWK; 8K7B; 8K7C
• EC Number: 7.6.2.5
• Pfam ID: PF00664 ; PF00005 ; PF16185
• Sequence:
  MVTVGNYCEAEGPVGPAWMQDGLSPCFFFTLVPSTRMALGTLALVLALPCRRRERPAGAD
  SLSWGAGPRISPYVLQLLLATLQAALPLAGLAGRVGTARGAPLPSYLLLASVLESLAGAC
  GLWLLVVERSQARQRLAMGIWIKFRHSPGLLLLWTVAFAAENLALVSWNSPQWWWARADL
  GQQVQFSLWVLRYVVSGGLFVLGLWAPGLRPQSYTLQVHEEDQDVERSQVRSAAQQSTWR
  DFGRKLRLLSGYLWPRGSPALQLVVLICLGLMGLERALNVLVPIFYRNIVNLLTEKAPWN
  SLAWTVTSYVFLKFLQGGGTGSTGFVSNLRTFLWIRVQQFTSRRVELLIFSHLHELSLRW
  HLGRRTGEVLRIADRGTSSVTGLLSYLVFNVIPTLADIIIGIIYFSMFFNAWFGLIVFLC
  MSLYLTLTIVVTEWRTKFRRAMNTQENATRARAVDSLLNFETVKYYNAESYEVERYREAI
  IKYQGLEWKSSASLVLLNQTQNLVIGLGLLAGSLLCAYFVTEQKLQVGDYVLFGTYIIQL
  YMPLNWFGTYYRMIQTNFIDMENMFDLLKEETEVKDLPGAGPLRFQKGRIEFENVHFSYA
  DGRETLQDVSFTVMPGQTLALVGPSGAGKSTILRLLFRFYDISSGCIRIDGQDISQVTQA
  SLRSHIGVVPQDTVLFNDTIADNIRYGRVTAGNDEVEAAAQAAGIHDAIMAFPEGYRTQV
  GERGLKLSGGEKQRVAIARTILKAPGIILLDEATSALDTSNERAIQASLAKVCANRTTIV
  VAHRLSTVVNADQILVIKDGCIVERGRHEALLSRGGVYADMWQLQQGQEETSEDTKPQTM
  ER
• Function: ATP-dependent transporter that catalyzes the transport of a broad-spectrum of porphyrins from the cytoplasm to the extracellular space through the plasma membrane or into the vesicle lumen. May also function as an ATP-dependent importer of porphyrins from the cytoplasm into the mitochondria, in turn may participate in the de novo heme biosynthesis regulation and in the coordination of heme and iron homeostasis during phenylhydrazine stress. May also play a key role in the early steps of melanogenesis producing PMEL amyloid fibrils. In vitro, it confers to cells a resistance to toxic metal such as arsenic and cadmium and against chemotherapeutics agent such as 5-fluorouracil, SN-38 and vincristin. In addition may play a role in the transition metal homeostasis.
• Tissue Specificity: Widely expressed. High expression is detected in the retinal epithelium . Expressed in mature erythrocytes .
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway:
  Defective ABCB6 causes MCOPCB7 (R-HSA-5683371)
  Mitochondrial ABC transporters (R-HSA-1369007)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dyschromatosis universalis hereditaria	DIS5MQWA	Supportive	Autosomal dominant	[1]
Familial pseudohyperkalemia	DISROQZH	Supportive	Autosomal dominant	[2]
Microphthalmia, isolated, with coloboma	DISLSEUJ	Supportive	Autosomal dominant	[3]
Dyschromatosis universalis hereditaria 3	DISQKSEL	Limited	Autosomal dominant	[1]
Microphthalmia, isolated, with coloboma 7	DISJESC5	Limited	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	ATP-binding cassette sub-family B member 6 (ABCB6) decreases the response to substance of Irinotecan.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[13]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[7]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[14]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[15]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[16]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[24]
Heme	DMGC287	Investigative	Heme increases the expression of ATP-binding cassette sub-family B member 6 (ABCB6).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-binding cassette sub-family B member 6 (ABCB6).	[18]

References

• [1] Mutations in ABCB6 cause dyschromatosis universalis hereditaria. J Invest Dermatol. 2013 Sep;133(9):2221-8. doi: 10.1038/jid.2013.145. Epub 2013 Mar 21.
• [2] Missense mutations in the ABCB6 transporter cause dominant familial pseudohyperkalemia. Am J Hematol. 2013 Jan;88(1):66-72. doi: 10.1002/ajh.23357. Epub 2012 Nov 24.
• [3] ABCB6 mutations cause ocular coloboma. Am J Hum Genet. 2012 Jan 13;90(1):40-8. doi: 10.1016/j.ajhg.2011.11.026. Epub 2012 Jan 5.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Evaluation of drug transporters' significance for multidrug resistance in head and neck squamous cell carcinoma. Head Neck. 2011 Jul;33(7):959-68. doi: 10.1002/hed.21559. Epub 2010 Aug 24.
• [8] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] 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.
• [13] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [14] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [15] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [16] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [23] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [24] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [25] Identification of a mammalian mitochondrial porphyrin transporter. Nature. 2006 Oct 5;443(7111):586-9. doi: 10.1038/nature05125. Epub 2006 Sep 27.
• [26] Expression of ABCB6 is related to resistance to 5-FU, SN-38 and vincristine. Anticancer Res. 2014 Sep;34(9):4767-73.