Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIJ76XW)

• DOT Name: ATP-binding cassette sub-family G member 8 (ABCG8)
• Synonyms: EC 7.6.2.-; Sterolin-2
• Gene Name: ABCG8
• Related Disease:
  Cholecystitis
  Gallbladder cancer
  Gallbladder carcinoma
  Low phospholipid associated cholelithiasis
  Sitosterolemia
  Sitosterolemia 1
  Biliary tract cancer
  Cholangiocarcinoma
  Cholestasis
  Familial hypercholesterolemia
  Gallbladder disease
  Gaucher disease type I
  Hemolytic anemia
  High blood pressure
  Homozygous familial hypercholesterolemia
  Hypercholesterolemia, familial, 1
  Hyperlipidemia
  Inherited bleeding disorder, platelet-type
  Non-alcoholic fatty liver disease
  Squamous cell carcinoma
  Type-1/2 diabetes
  Vascular disease
  Chronic renal failure
  Coronary atherosclerosis
  End-stage renal disease
  Gerstmann-Straussler-Scheinker syndrome
  Nephropathy
  Cardiovascular disease
  Coronary heart disease
  Intrahepatic cholestasis of pregnancy
• UniProt ID: ABCG8_HUMAN
• PDB ID: 5DO7; 7JR7; 7R87; 7R88; 7R89; 7R8A; 7R8B; 8CUB
• EC Number: 7.6.2.-
• Pfam ID: PF01061 ; PF19055 ; PF00005
• Sequence:
  MAGKAAEERGLPKGATPQDTSGLQDRLFSSESDNSLYFTYSGQPNTLEVRDLNYQVDLAS
  QVPWFEQLAQFKMPWTSPSCQNSCELGIQNLSFKVRSGQMLAIIGSSGCGRASLLDVITG
  RGHGGKIKSGQIWINGQPSSPQLVRKCVAHVRQHNQLLPNLTVRETLAFIAQMRLPRTFS
  QAQRDKRVEDVIAELRLRQCADTRVGNMYVRGLSGGERRRVSIGVQLLWNPGILILDEPT
  SGLDSFTAHNLVKTLSRLAKGNRLVLISLHQPRSDIFRLFDLVLLMTSGTPIYLGAAQHM
  VQYFTAIGYPCPRYSNPADFYVDLTSIDRRSREQELATREKAQSLAALFLEKVRDLDDFL
  WKAETKDLDEDTCVESSVTPLDTNCLPSPTKMPGAVQQFTTLIRRQISNDFRDLPTLLIH
  GAEACLMSMTIGFLYFGHGSIQLSFMDTAALLFMIGALIPFNVILDVISKCYSERAMLYY
  ELEDGLYTTGPYFFAKILGELPEHCAYIIIYGMPTYWLANLRPGLQPFLLHFLLVWLVVF
  CCRIMALAAAALLPTFHMASFFSNALYNSFYLAGGFMINLSSLWTVPAWISKVSFLRWCF
  EGLMKIQFSRRTYKMPLGNLTIAVSGDKILSVMELDSYPLYAIYLIVIGLSGGFMVLYYV
  SLRFIKQKPSQDW
• 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 the dietary 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 ABCG5 has ATPase activity.
• Tissue Specificity: Predominantly expressed in the liver . Low expression levels in the small intestine and colon . Very low levels in other tissues, including brain, heart and spleen .
• 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

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cholecystitis	DISG024R	Definitive	Altered Expression	[1]
Gallbladder cancer	DISXJUAF	Definitive	Genetic Variation	[1]
Gallbladder carcinoma	DISD6ACL	Definitive	Genetic Variation	[1]
Low phospholipid associated cholelithiasis	DISKWFFA	Definitive	Genetic Variation	[2]
Sitosterolemia	DISTCQGB	Definitive	Autosomal recessive	[3]
Sitosterolemia 1	DISOKUSB	Definitive	Autosomal recessive	[4]
Biliary tract cancer	DISBNYQL	Strong	Genetic Variation	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Genetic Variation	[5]
Cholestasis	DISDJJWE	Strong	Biomarker	[6]
Familial hypercholesterolemia	DISC06IX	Strong	Biomarker	[7]
Gallbladder disease	DISA6W3T	Strong	Genetic Variation	[8]
Gaucher disease type I	DIS87KKY	Strong	Genetic Variation	[9]
Hemolytic anemia	DIS803XQ	Strong	Altered Expression	[10]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[11]
Homozygous familial hypercholesterolemia	DISRCNCF	Strong	Genetic Variation	[12]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Biomarker	[7]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[13]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Biomarker	[14]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[15]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[16]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[17]
Vascular disease	DISVS67S	Strong	Genetic Variation	[18]
Chronic renal failure	DISGG7K6	moderate	Genetic Variation	[19]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[11]
End-stage renal disease	DISXA7GG	moderate	Genetic Variation	[19]
Gerstmann-Straussler-Scheinker syndrome	DISIO6KC	moderate	Genetic Variation	[1]
Nephropathy	DISXWP4P	moderate	Genetic Variation	[19]
Cardiovascular disease	DIS2IQDX	Limited	Genetic Variation	[20]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[21]
Intrahepatic cholestasis of pregnancy	DISMHS5F	Limited	Biomarker	[22]

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 8 (ABCG8) affects the export of ANW-32821.	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of ATP-binding cassette sub-family G member 8 (ABCG8).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[26]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[24]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[27]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[28]
Lindane	DMB8CNL	Approved	Lindane increases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[29]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[30]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP-binding cassette sub-family G member 8 (ABCG8).	[32]

References

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• [2] ABCB4 mutations underlie hormonal cholestasis but not pediatric idiopathic gallstones.World J Gastroenterol. 2014 May 21;20(19):5867-74. doi: 10.3748/wjg.v20.i19.5867.
• [3] 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.
• [4] Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000 Dec 1;290(5497):1771-5. doi: 10.1126/science.290.5497.1771.
• [5] Cholesterol metabolism gene polymorphisms and the risk of biliary tract cancers and stones: a population-based case-control study in Shanghai, China.Carcinogenesis. 2011 Jan;32(1):58-62. doi: 10.1093/carcin/bgq194. Epub 2010 Nov 9.
• [6] Effect of maternal cholestasis and treatment with ursodeoxycholic acid on the expression of genes involved in the secretion of biliary lipids by the neonatal rat liver.Life Sci. 2006 Aug 1;79(10):1014-9. doi: 10.1016/j.lfs.2006.05.012. Epub 2006 May 20.
• [7] Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype.Circ J. 2019 Aug 23;83(9):1917-1924. doi: 10.1253/circj.CJ-19-0317. Epub 2019 Jul 20.
• [8] Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array.Eur J Hum Genet. 2016 Jan;24(1):106-12. doi: 10.1038/ejhg.2015.63. Epub 2015 Apr 29.
• [9] Cholelithiasis in Patients with Gaucher Disease type 1: Risk Factors and the Role of ABCG5/ABCG8 Gene Variants.J Gastrointestin Liver Dis. 2016 Dec;25(4):447-455. doi: 10.15403/jgld.2014.1121.254.zim.
• [10] A novel mutation of ABCG5 gene in a Turkish boy with phytosterolemia presenting with macrotrombocytopenia and stomatocytosis.Pediatr Blood Cancer. 2014 Aug;61(8):1457-9. doi: 10.1002/pbc.24934. Epub 2014 Jan 16.
• [11] Effect of genetic variant (rs11887534) in ABCG8 gene in coronary artery disease and response to atorvastatin therapy. Dis Markers. 2010;28(5):307-13.
• [12] Genetic variations at ABCG5/G8 genes modulate plasma lipids concentrations in patients with familial hypercholesterolemia.Atherosclerosis. 2010 Jun;210(2):486-92. doi: 10.1016/j.atherosclerosis.2010.01.010. Epub 2010 Jan 22.
• [13] Hyperlipidemia Determines Dysfunctional HDL Production and Impedes Cholesterol Efflux in the Small Intestine: Alleviation by Ginger Extract.Mol Nutr Food Res. 2019 Oct;63(19):e1900029. doi: 10.1002/mnfr.201900029. Epub 2019 Jul 16.
• [14] Two novel variants of the ABCG5 gene cause xanthelasmas and macrothrombocytopenia: a brief review of hematologic abnormalities of sitosterolemia.J Thromb Haemost. 2017 Sep;15(9):1859-1866. doi: 10.1111/jth.13777. Epub 2017 Aug 5.
• [15] Modulation of xenobiotic nuclear receptors in high-fat diet induced non-alcoholic fatty liver disease.Toxicology. 2018 Dec 1;410:199-213. doi: 10.1016/j.tox.2018.08.007. Epub 2018 Aug 16.
• [16] Genetic variants at 6p21.1 and 7p15.3 are associated with risk of multiple cancers in Han Chinese.Am J Hum Genet. 2012 Nov 2;91(5):928-34. doi: 10.1016/j.ajhg.2012.09.009. Epub 2012 Oct 25.
• [17] ABCG5 and ABCG8 gene polymorphisms in type 2 diabetes mellitus in the Turkish population.Can J Diabetes. 2015 Oct;39(5):405-10. doi: 10.1016/j.jcjd.2015.04.004. Epub 2015 Jun 16.
• [18] Frequencies of four ATP-binding cassette transporter G8 polymorphisms in patients with ischemic vascular diseases.Genet Test Mol Biomarkers. 2010 Oct;14(5):667-72. doi: 10.1089/gtmb.2010.0035. Epub 2010 Sep 20.
• [19] ABCG8 polymorphisms and renal disease in type 2 diabetic patients.Metabolism. 2015 Jun;64(6):713-9. doi: 10.1016/j.metabol.2015.03.005. Epub 2015 Mar 14.
• [20] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [21] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [22] Hepatic expression of detoxification enzymes is decreased in human obstructive cholestasis due to gallstone biliary obstruction.PLoS One. 2015 Mar 23;10(3):e0120055. doi: 10.1371/journal.pone.0120055. eCollection 2015.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [27] 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.
• [28] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [29] Organochloride pesticides induced hepatic ABCG5/G8 expression and lipogenesis in Chinese patients with gallstone disease. Oncotarget. 2016 Jun 7;7(23):33689-702. doi: 10.18632/oncotarget.9399.
• [30] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [33] 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.