Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAM94ID)

• DOT Name: Heme transporter FLVCR2 (FLVCR2)
• Synonyms: Calcium-chelate transporter; CCT; Feline leukemia virus subgroup C receptor-related protein 2
• Gene Name: FLVCR2
• Related Disease:
  Fowler syndrome
  Hydranencephaly
  Vascular disease
• UniProt ID: FLVC2_HUMAN
• Pfam ID: PF07690
• Sequence:
  MVNEGPNQEESDDTPVPESALQADPSVSVHPSVSVHPSVSINPSVSVHPSSSAHPSALAQ
  PSGLAHPSSSGPEDLSVIKVSRRRWAVVLVFSCYSMCNSFQWIQYGSINNIFMHFYGVSA
  FAIDWLSMCYMLTYIPLLLPVAWLLEKFGLRTIALTGSALNCLGAWVKLGSLKPHLFPVT
  VVGQLICSVAQVFILGMPSRIASVWFGANEVSTACSVAVFGNQLGIAIGFLVPPVLVPNI
  EDRDELAYHISIMFYIIGGVATLLLILVIIVFKEKPKYPPSRAQSLSYALTSPDASYLGS
  IARLFKNLNFVLLVITYGLNAGAFYALSTLLNRMVIWHYPGEEVNAGRIGLTIVIAGMLG
  AVISGIWLDRSKTYKETTLVVYIMTLVGMVVYTFTLNLGHLWVVFITAGTMGFFMTGYLP
  LGFEFAVELTYPESEGISSGLLNISAQVFGIIFTISQGQIIDNYGTKPGNIFLCVFLTLG
  AALTAFIKADLRRQKANKETLENKLQEEEEESNTSKVPTAVSEDHL
• Function: Putative heme b importer/sensor involved in heme homeostasis in response to the metabolic state of the cell and to diet. May act as a sensor of cytosolic and/or mitochondrial heme levels to regulate mitochondrial respiration processes, ATP synthesis and thermogenesis. At low heme levels, interacts with components of electron transfer chain (ETC) complexes and ATP2A2, leading to ubiquitin-mediated degradation of ATP2A2 and inhibition of thermogenesis. Upon heme binding, dissociates from ETC complexes to allow switching from mitochondrial ATP synthesis to thermogenesis. Alternatively, in coordination with ATP2A2 may mediate calcium transport and signaling in response to heme.
• Tissue Specificity: Expressed in non-hematopoietic tissues, with relative abundant expression in brain, placenta, lung, liver and kidney . Also expressed in hematopoietic tissues (fetal liver, spleen, lymph node, thymus, leukocytes and bone marrow) . Found in acidophil cells of the pituitary that secrete growth hormone and prolactin (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fowler syndrome	DIS5441L	Definitive	Autosomal recessive	[1]
Hydranencephaly	DISE02PO	Strong	Genetic Variation	[2]
Vascular disease	DISVS67S	Strong	Genetic Variation	[3]

19 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 Heme transporter FLVCR2 (FLVCR2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Heme transporter FLVCR2 (FLVCR2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Heme transporter FLVCR2 (FLVCR2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Heme transporter FLVCR2 (FLVCR2).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[14]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of Heme transporter FLVCR2 (FLVCR2).	[10]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[10]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Heme transporter FLVCR2 (FLVCR2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Heme transporter FLVCR2 (FLVCR2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Heme transporter FLVCR2 (FLVCR2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Heme transporter FLVCR2 (FLVCR2).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Heme transporter FLVCR2 (FLVCR2).	[20]

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 decreases the methylation of Heme transporter FLVCR2 (FLVCR2).	[15]

References

• [1] Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome). Am J Hum Genet. 2010 Mar 12;86(3):471-8. doi: 10.1016/j.ajhg.2010.02.004. Epub 2010 Mar 4.
• [2] Hydranencephaly in a newborn with a FLVCR2 mutation and prenatal exposure to cocaine.Birth Defects Res A Clin Mol Teratol. 2015 Jan;103(1):45-50. doi: 10.1002/bdra.23288. Epub 2014 Jul 30.
• [3] High-throughput sequencing of a 4.1Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy.Hum Mutat. 2010 Oct;31(10):1134-41. doi: 10.1002/humu.21329.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] 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.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [15] 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.
• [16] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [17] 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.
• [18] 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.
• [19] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [20] 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.