Details of Drug Off-Target (DOT)

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

• DOT Name: Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7)
• Synonyms: ATP-binding cassette sub-family B member 7, mitochondrial; ATP-binding cassette transporter 7; ABC transporter 7 protein
• Gene Name: ABCB7
• Related Disease:
  X-linked sideroblastic anemia with ataxia
  Mitochondrial disease
• UniProt ID: ABCB7_HUMAN
• PDB ID: 7VGF
• Pfam ID: PF00664 ; PF00005
• Sequence:
  MALLAMHSWRWAAAAAAFEKRRHSAILIRPLVSVSGSGPQWRPHQLGALGTARAYQIPES
  LKSITWQRLGKGNSGQFLDAAKALQVWPLIEKRTCWHGHAGGGLHTDPKEGLKDVDTRKI
  IKAMLSYVWPKDRPDLRARVAISLGFLGGAKAMNIVVPFMFKYAVDSLNQMSGNMLNLSD
  APNTVATMATAVLIGYGVSRAGAAFFNEVRNAVFGKVAQNSIRRIAKNVFLHLHNLDLGF
  HLSRQTGALSKAIDRGTRGISFVLSALVFNLLPIMFEVMLVSGVLYYKCGAQFALVTLGT
  LGTYTAFTVAVTRWRTRFRIEMNKADNDAGNAAIDSLLNYETVKYFNNERYEAQRYDGFL
  KTYETASLKSTSTLAMLNFGQSAIFSVGLTAIMVLASQGIVAGTLTVGDLVMVNGLLFQL
  SLPLNFLGTVYRETRQALIDMNTLFTLLKVDTQIKDKVMASPLQITPQTATVAFDNVHFE
  YIEGQKVLSGISFEVPAGKKVAIVGGSGSGKSTIVRLLFRFYEPQKGSIYLAGQNIQDVS
  LESLRRAVGVVPQDAVLFHNTIYYNLLYGNISASPEEVYAVAKLAGLHDAILRMPHGYDT
  QVGERGLKLSGGEKQRVAIARAILKDPPVILYDEATSSLDSITEETILGAMKDVVKHRTS
  IFIAHRLSTVVDADEIIVLDQGKVAERGTHHGLLANPHSIYSEMWHTQSSRVQNHDNPKW
  EAKKENISKEEERKKLQEEIVNSVKGCGNCSC
• Function: Exports glutathione-coordinated iron-sulfur clusters such as [2Fe-2S]-(GS)4 cluster from the mitochondria to the cytosol in an ATP-dependent manner allowing the assembly of the cytosolic iron-sulfur (Fe/S) cluster-containing proteins and participates in iron homeostasis. Moreover, through a functional complex formed of ABCB7, FECH and ABCB10, also plays a role in the cellular iron homeostasis, mitochondrial function and heme biosynthesis. In cardiomyocytes, regulates cellular iron homeostasis and cellular reactive oxygen species (ROS) levels through its interaction with COX4I1. May also play a role in hematopoiesis.
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway:
  Cytosolic iron-sulfur cluster assembly (R-HSA-2564830)
  Mitochondrial ABC transporters (R-HSA-1369007)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked sideroblastic anemia with ataxia	DISJMVOX	Definitive	X-linked recessive	[1]
Mitochondrial disease	DISKAHA3	Moderate	X-linked	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7) affects the response to substance of Cisplatin.	[12]
Capecitabine	DMTS85L	Approved	Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7) decreases the response to substance of Capecitabine.	[13]

8 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 Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[9]
Gallium nitrate	DMF9O6B	Approved	Gallium nitrate decreases the expression of Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[10]

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 Iron-sulfur clusters transporter ABCB7, mitochondrial (ABCB7).	[11]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] 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.
• [8] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [9] 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.
• [10] Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med. 2008 Sep 15;45(6):763-72.
• [11] 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.
• [12] Role of transporter genes in cisplatin resistance. In Vivo. 2008 May-Jun;22(3):279-83.
• [13] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.