Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1OMY93)

• DOT Name: ATP-binding cassette sub-family G member 5 (ABCG5)
• Synonyms: EC 7.6.2.-; Sterolin-1
• Gene Name: ABCG5
• Related Disease:
  Sitosterolemia
  Sitosterolemia 1
• UniProt ID: ABCG5_HUMAN
• PDB ID: 5DO7; 7JR7; 7R87; 7R88; 7R89; 7R8A; 7R8B; 8CUB
• EC Number: 7.6.2.-
• Pfam ID: PF01061 ; PF19055 ; PF00005
• Sequence:
  MGDLSSLTPGGSMGLQVNRGSQSSLEGAPATAPEPHSLGILHASYSVSHRVRPWWDITSC
  RQQWTRQILKDVSLYVESGQIMCILGSSGSGKTTLLDAMSGRLGRAGTFLGEVYVNGRAL
  RREQFQDCFSYVLQSDTLLSSLTVRETLHYTALLAIRRGNPGSFQKKVEAVMAELSLSHV
  ADRLIGNYSLGGISTGERRRVSIAAQLLQDPKVMLFDEPTTGLDCMTANQIVVLLVELAR
  RNRIVVLTIHQPRSELFQLFDKIAILSFGELIFCGTPAEMLDFFNDCGYPCPEHSNPFDF
  YMDLTSVDTQSKEREIETSKRVQMIESAYKKSAICHKTLKNIERMKHLKTLPMVPFKTKD
  SPGVFSKLGVLLRRVTRNLVRNKLAVITRLLQNLIMGLFLLFFVLRVRSNVLKGAIQDRV
  GLLYQFVGATPYTGMLNAVNLFPVLRAVSDQESQDGLYQKWQMMLAYALHVLPFSVVATM
  IFSSVCYWTLGLHPEVARFGYFSAALLAPHLIGEFLTLVLLGIVQNPNIVNSVVALLSIA
  GVLVGSGFLRNIQEMPIPFKIISYFTFQKYCSEILVVNEFYGLNFTCGSSNVSVTTNPMC
  AFTQGIQFIEKTCPGATSRFTMNFLILYSFIPALVILGIVVFKIRDHLISR
• Function: ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane. Plays an essential role in the selective transport of dietary plant sterols and cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile. Required for normal sterol homeostasis. The heterodimer with ABCG8 has ATPase activity.
• Tissue Specificity: Strongly expressed in the liver, lower levels in the small intestine and colon.
• KEGG Pathway:
  ABC transporters (hsa02010)
  Fat digestion and absorption (hsa04975)
  Bile secretion (hsa04976)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  Defective ABCG8 causes GBD4 and sitosterolemia (R-HSA-5679090)
  Defective ABCG5 causes sitosterolemia (R-HSA-5679096)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sitosterolemia	DISTCQGB	Definitive	Autosomal recessive	[1]
Sitosterolemia 1	DISOKUSB	Definitive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	ATP-binding cassette sub-family G member 5 (ABCG5) affects the response to substance of Temozolomide.	[18]
DTI-015	DMXZRW0	Approved	ATP-binding cassette sub-family G member 5 (ABCG5) affects the response to substance of DTI-015.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
ANW-32821	DMMJOZD	Phase 2	ATP-binding cassette sub-family G member 5 (ABCG5) affects the export of ANW-32821.	[19]

19 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 G member 5 (ABCG5).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[9]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[10]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[11]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[12]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[10]
Clavulanate	DM2FGRT	Approved	Clavulanate decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[13]
Cholic acid	DM7OKQV	Approved	Cholic acid increases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[13]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[9]
	DM9CEI5		increases the expression of ATP-binding cassette sub-family G member 5 (ABCG5).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ATP-binding cassette sub-family G member 5 (ABCG5).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of ATP-binding cassette sub-family G member 5 (ABCG5).	[16]

References

• [1] 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.
• [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] 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.
• [4] 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.
• [5] Repression of hepatocyte nuclear factor 4 alpha by AP-1 underlies dyslipidemia associated with retinoic acid. J Lipid Res. 2019 Apr;60(4):794-804. doi: 10.1194/jlr.M088880. Epub 2019 Feb 1.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures. Toxicol Sci. 2014 Oct;141(2):538-46. doi: 10.1093/toxsci/kfu151. Epub 2014 Jul 23.
• [11] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [12] Fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients. Eur J Clin Pharmacol. 2004 Feb;59(12):855-61. doi: 10.1007/s00228-003-0704-1. Epub 2003 Dec 18.
• [13] Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [19] Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease. Scand J Gastroenterol Suppl. 2004;(241):60-9. doi: 10.1080/00855920410011022.