Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKH9YQZ)

• DOT Name: Glucosylceramide transporter ABCA12 (ABCA12)
• Synonyms: EC 7.6.2.1; ATP-binding cassette sub-family A member 12; ATP-binding cassette transporter 12; ATP-binding cassette 12
• Gene Name: ABCA12
• Related Disease:
  Autosomal recessive congenital ichthyosis 4A
  Autosomal recessive congenital ichthyosis 4B
  Congenital ichthyosiform erythroderma
  Lamellar ichthyosis
• UniProt ID: ABCAC_HUMAN
• EC Number: 7.6.2.1
• Pfam ID: PF12698 ; PF00005
• Sequence:
  MASLFHQLQILVWKNWLGVKRQPLWTLVLILWPVIIFIILAITRTKFPPTAKPTCYLAPR
  NLPSTGFFPFLQTLLCDTDSKCKDTPYGPQDLLRRKGIDDALFKDSEILRKSSNLDKDSS
  LSFQSTQVPERRHASLATVFPSPSSDLEIPGTYTFNGSQVLARILGLEKLLKQNSTSEDI
  RRELCDSYSGYIVDDAFSWTFLGRNVFNKFCLSNMTLLESSLQELNKQFSQLSSDPNNQK
  IVFQEIVRMLSFFSQVQEQKAVWQLLSSFPNVFQNDTSLSNLFDVLRKANSVLLVVQKVY
  PRFATNEGFRTLQKSVKHLLYTLDSPAQGDSDNITHVWNEDDGQTLSPSSLAAQLLILEN
  FEDALLNISANSPYIPYLACVRNVTDSLARGSPENLRLLQSTIRFKKSFLRNGSYEDYFP
  PVPEVLKSKLSQLRNLTELLCESETFSLIEKSCQLSDMSFGSLCEESEFDLQLLEAAELG
  TEIAASLLYHDNVISKKVRDLLTGDPSKINLNMDQFLEQALQMNYLENITQLIPIIEAML
  HVNNSADASEKPGQLLEMFKNVEELKEDLRRTTGMSNRTIDKLLAIPIPDNRAEIISQVF
  WLHSCDTNITTPKLEDAMKEFCNLSLSERSRQSYLIGLTLLHYLNIYNFTYKVFFPRKDQ
  KPVEKMMELFIRLKEILNQMASGTHPLLDKMRSLKQMHLPRSVPLTQAMYRSNRMNTPQG
  SFSTISQALCSQGITTEYLTAMLPSSQRPKGNHTKDFLTYKLTKEQIASKYGIPINSTPF
  CFSLYKDIINMPAGPVIWAFLKPMLLGRILYAPYNPVTKAIMEKSNVTLRQLAELREKSQ
  EWMDKSPLFMNSFHLLNQAIPMLQNTLRNPFVQVFVKFSVGLDAVELLKQIDELDILRLK
  LENNIDIIDQLNTLSSLTVNISSCVLYDRIQAAKTIDEMEREAKRLYKSNELFGSVIFKL
  PSNRSWHRGYDSGNVFLPPVIKYTIRMSLKTAQTTRSLRTKIWAPGPHNSPSHNQIYGRA
  FIYLQDSIERAIIELQTGRNSQEIAVQVQAIPYPCFMKDNFLTSVSYSLPIVLMVAWVVF
  IAAFVKKLVYEKDLRLHEYMKMMGVNSCSHFFAWLIESVGFLLVTIVILIIILKFGNILP
  KTNGFILFLYFSDYSFSVIAMSYLISVFFNNTNIAALIGSLIYIIAFFPFIVLVTVENEL
  SYVLKVFMSLLSPTAFSYASQYIARYEEQGIGLQWENMYTSPVQDDTTSFGWLCCLILAD
  SFIYFLIAWYVRNVFPGTYGMAAPWYFPILPSYWKERFGCAEVKPEKSNGLMFTNIMMQN
  TNPSASPEYMFSSNIEPEPKDLTVGVALHGVTKIYGSKVAVDNLNLNFYEGHITSLLGPN
  GAGKTTTISMLTGLFGASAGTIFVYGKDIKTDLHTVRKNMGVCMQHDVLFSYLTTKEHLL
  LYGSIKVPHWTKKQLHEEVKRTLKDTGLYSHRHKRVGTLSGGMKRKLSISIALIGGSRVV
  ILDEPSTGVDPCSRRSIWDVISKNKTARTIILSTHHLDEAEVLSDRIAFLEQGGLRCCGS
  PFYLKEAFGDGYHLTLTKKKSPNLNANAVCDTMAVTAMIQSHLPEAYLKEDIGGELVYVL
  PPFSTKVSGAYLSLLRALDNGMGDLNIGCYGISDTTVEEVFLNLTKESQKNSAMSLEHLT
  QKKIGNSNANGISTPDDLSVSSSNFTDRDDKILTRGERLDGFGLLLKKIMAILIKRFHHT
  RRNWKGLIAQVILPIVFVTTAMGLGTLRNSSNSYPEIQISPSLYGTSEQTAFYANYHPST
  EALVSAMWDFPGIDNMCLNTSDLQCLNKDSLEKWNTSGEPITNFGVCSCSENVQECPKFN
  YSPPHRRTYSSQVIYNLTGQRVENYLISTANEFVQKRYGGWSFGLPLTKDLRFDITGVPA
  NRTLAKVWYDPEGYHSLPAYLNSLNNFLLRVNMSKYDAARHGIIMYSHPYPGVQDQEQAT
  ISSLIDILVALSILMGYSVTTASFVTYVVREHQTKAKQLQHISGIGVTCYWVTNFIYDMV
  FYLVPVAFSIGIIAIFKLPAFYSENNLGAVSLLLLLFGYATFSWMYLLAGLFHETGMAFI
  TYVCVNLFFGINSIVSLSVVYFLSKEKPNDPTLELISETLKRIFLIFPQFCFGYGLIELS
  QQQSVLDFLKAYGVEYPNETFEMNKLGAMFVALVSQGTMFFSLRLLINESLIKKLRLFFR
  KFNSSHVRETIDEDEDVRAERLRVESGAAEFDLVQLYCLTKTYQLIHKKIIAVNNISIGI
  PAGECFGLLGVNGAGKTTIFKMLTGDIIPSSGNILIRNKTGSLGHVDSHSSLVGYCPQED
  ALDDLVTVEEHLYFYARVHGIPEKDIKETVHKLLRRLHLMPFKDRATSMCSYGTKRKLST
  ALALIGKPSILLLDEPSSGMDPKSKRHLWKIISEEVQNKCSVILTSHSMEECEALCTRLA
  IMVNGKFQCIGSLQHIKSRFGRGFTVKVHLKNNKVTMETLTKFMQLHFPKTYLKDQHLSM
  LEYHVPVTAGGVANIFDLLETNKTALNITNFLVSQTTLEEVFINFAKDQKSYETADTSSQ
  GSTISVDSQDDQMES
• Function: Transports lipids such as glucosylceramides from the outer to the inner leaflet of lamellar granules (LGs) membrane, whereby the lipids are finally transported to the keratinocyte periphery via the trans-Golgi network and LGs and released to the apical surface of the granular keratinocytes to form lipid lamellae in the stratum corneum of the epidermis, which is essential for skin barrier function. In the meantime, participates in the transport of the lamellar granules-associated proteolytic enzymes, in turn regulates desquamation and keratinocyte differentiation. Furthermore, is essential for the regulation of cellular cholesterol homeostasis by regulating ABCA1-dependent cholesterol efflux from macrophages through interaction with NR1H2 and ABCA1. Plays pleiotropic roles in regulating glucose stimulated insulin secretion from beta cells, regulating the morphology and fusion of insulin granules, lipid raft abundance and the actin cytoskeleton. Also involved in lung surfactant biogenesis.
• Tissue Specificity: Mainly expressed in the stomach, placenta, testis and fetal brain . Expressed in the upper epidermal layers, mainly the granular layers, of skin . Expressed throughout the normal interfollicular epidermis with prominent expression in the stratum granulosum . Expressed in alpha and beta cells of pancreatic islets .
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway:
  Defective ABCA12 causes ARCI4B (R-HSA-5682294)
  ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive congenital ichthyosis 4A	DISYEOAR	Strong	Autosomal recessive	[1]
Autosomal recessive congenital ichthyosis 4B	DIS687J0	Strong	Autosomal recessive	[1]
Congenital ichthyosiform erythroderma	DISV8HQX	Supportive	Autosomal recessive	[2]
Lamellar ichthyosis	DIS714UN	Supportive	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Glucosylceramide transporter ABCA12 (ABCA12).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Glucosylceramide transporter ABCA12 (ABCA12).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[13]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[15]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[16]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[5]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Glucosylceramide transporter ABCA12 (ABCA12).	[19]

References

• [1] 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.
• [2] Novel compound heterozygous nonsense and missense ABCA12 mutations lead to nonbullous congenital ichthyosiform erythroderma. Br J Dermatol. 2008 Apr;158(4):864-7. doi: 10.1111/j.1365-2133.2008.08439.x. Epub 2008 Feb 16.
• [3] Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet. 2013 Feb;21(2):123-33. doi: 10.1038/ejhg.2012.121. Epub 2012 Jun 27.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [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] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [15] Identification of cornifelin and early growth response-1 gene as novel biomarkers for in vitro eye irritation using a 3D reconstructed human cornea model MCTT HCE?. Arch Toxicol. 2015 Sep;89(9):1589-98. doi: 10.1007/s00204-014-1390-8. Epub 2014 Nov 7.
• [16] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [17] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.