Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCWQ54I)

• DOT Name: ATP-binding cassette sub-family C member 8 (ABCC8)
• Synonyms: Sulfonylurea receptor 1
• Gene Name: ABCC8
• Related Disease:
  Diabetes mellitus, permanent neonatal 3
  Familial hyperinsulinism
  Hyperinsulinemic hypoglycemia, familial, 1
  Monogenic diabetes
  Diabetes mellitus, transient neonatal, 2
  Hypoglycemia, leucine-induced
  Obsolete diabetes mellitus, noninsulin-dependent
  Permanent neonatal diabetes mellitus
  Transient neonatal diabetes mellitus
  Pulmonary arterial hypertension
  Autosomal dominant hyperinsulinism due to SUR1 deficiency
  Autosomal recessive hyperinsulinism due to SUR1 deficiency
  DEND syndrome
  Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency
  Maturity-onset diabetes of the young
  Non-insulin dependent diabetes
• UniProt ID: ABCC8_HUMAN
• PDB ID: 6C3O; 6C3P; 7S5V; 7S5X; 7S5Y; 7S5Z; 7S60; 7S61
• Pfam ID: PF00664 ; PF00005
• Sequence:
  MPLAFCGSENHSAAYRVDQGVLNNGCFVDALNVVPHVFLLFITFPILFIGWGSQSSKVHI
  HHSTWLHFPGHNLRWILTFMLLFVLVCEIAEGILSDGVTESHHLHLYMPAGMAFMAAVTS
  VVYYHNIETSNFPKLLIALLVYWTLAFITKTIKFVKFLDHAIGFSQLRFCLTGLLVILYG
  MLLLVEVNVIRVRRYIFFKTPREVKPPEDLQDLGVRFLQPFVNLLSKGTYWWMNAFIKTA
  HKKPIDLRAIGKLPIAMRALTNYQRLCEAFDAQVRKDIQGTQGARAIWQALSHAFGRRLV
  LSSTFRILADLLGFAGPLCIFGIVDHLGKENDVFQPKTQFLGVYFVSSQEFLANAYVLAV
  LLFLALLLQRTFLQASYYVAIETGINLRGAIQTKIYNKIMHLSTSNLSMGEMTAGQICNL
  VAIDTNQLMWFFFLCPNLWAMPVQIIVGVILLYYILGVSALIGAAVIILLAPVQYFVATK
  LSQAQRSTLEYSNERLKQTNEMLRGIKLLKLYAWENIFRTRVETTRRKEMTSLRAFAIYT
  SISIFMNTAIPIAAVLITFVGHVSFFKEADFSPSVAFASLSLFHILVTPLFLLSSVVRST
  VKALVSVQKLSEFLSSAEIREEQCAPHEPTPQGPASKYQAVPLRVVNRKRPAREDCRGLT
  GPLQSLVPSADGDADNCCVQIMGGYFTWTPDGIPTLSNITIRIPRGQLTMIVGQVGCGKS
  SLLLAALGEMQKVSGAVFWSSLPDSEIGEDPSPERETATDLDIRKRGPVAYASQKPWLLN
  ATVEENIIFESPFNKQRYKMVIEACSLQPDIDILPHGDQTQIGERGINLSGGQRQRISVA
  RALYQHANVVFLDDPFSALDIHLSDHLMQAGILELLRDDKRTVVLVTHKLQYLPHADWII
  AMKDGTIQREGTLKDFQRSECQLFEHWKTLMNRQDQELEKETVTERKATEPPQGLSRAMS
  SRDGLLQDEEEEEEEAAESEEDDNLSSMLHQRAEIPWRACAKYLSSAGILLLSLLVFSQL
  LKHMVLVAIDYWLAKWTDSALTLTPAARNCSLSQECTLDQTVYAMVFTVLCSLGIVLCLV
  TSVTVEWTGLKVAKRLHRSLLNRIILAPMRFFETTPLGSILNRFSSDCNTIDQHIPSTLE
  CLSRSTLLCVSALAVISYVTPVFLVALLPLAIVCYFIQKYFRVASRDLQQLDDTTQLPLL
  SHFAETVEGLTTIRAFRYEARFQQKLLEYTDSNNIASLFLTAANRWLEVRMEYIGACVVL
  IAAVTSISNSLHRELSAGLVGLGLTYALMVSNYLNWMVRNLADMELQLGAVKRIHGLLKT
  EAESYEGLLAPSLIPKNWPDQGKIQIQNLSVRYDSSLKPVLKHVNALIAPGQKIGICGRT
  GSGKSSFSLAFFRMVDTFEGHIIIDGIDIAKLPLHTLRSRLSIILQDPVLFSGTIRFNLD
  PERKCSDSTLWEALEIAQLKLVVKALPGGLDAIITEGGENFSQGQRQLFCLARAFVRKTS
  IFIMDEATASIDMATENILQKVVMTAFADRTVVTIAHRVHTILSADLVIVLKRGAILEFD
  KPEKLLSRKDSVFASFVRADK
• Function: Subunit of the beta-cell ATP-sensitive potassium channel (KATP). Regulator of ATP-sensitive K(+) channels and insulin release.
• KEGG Pathway:
  ABC transporters (hsa02010)
  Insulin secretion (hsa04911)
  Type II diabetes mellitus (hsa04930)
• Reactome Pathway:
  Regulation of insulin secretion (R-HSA-422356)
  Defective ABCC8 can cause hypo- and hyper-glycemias (R-HSA-5683177)
  ATP sensitive Potassium channels (R-HSA-1296025)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetes mellitus, permanent neonatal 3	DIS322TS	Definitive	Semidominant	[1]
Familial hyperinsulinism	DISHQKQE	Definitive	Autosomal recessive	[2]
Hyperinsulinemic hypoglycemia, familial, 1	DIS5NBUS	Definitive	Semidominant	[1]
Monogenic diabetes	DISEB8Q0	Definitive	Semidominant	[2]
Diabetes mellitus, transient neonatal, 2	DISBIR6Z	Strong	Unknown	[3]
Hypoglycemia, leucine-induced	DISG8994	Strong	Autosomal dominant	[3]
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	Strong	Autosomal dominant	[3]
Permanent neonatal diabetes mellitus	DIS5AEXS	Strong	Autosomal recessive	[3]
Transient neonatal diabetes mellitus	DIST826V	Strong	Autosomal dominant	[3]
Pulmonary arterial hypertension	DISP8ZX5	Moderate	Autosomal dominant	[2]
Autosomal dominant hyperinsulinism due to SUR1 deficiency	DISGMI3Q	Supportive	Autosomal dominant	[4]
Autosomal recessive hyperinsulinism due to SUR1 deficiency	DISZXJA3	Supportive	Autosomal recessive	[5]
DEND syndrome	DISRNWGB	Supportive	Autosomal dominant	[6]
Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency	DISAE2IM	Supportive	Autosomal dominant	[7]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Autosomal dominant	[9]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	ATP-binding cassette sub-family C member 8 (ABCC8) affects the response to substance of Cisplatin.	[14]
Glimepiride	DM5FSJA	Approved	ATP-binding cassette sub-family C member 8 (ABCC8) increases the Blood glucose decreased ADR of Glimepiride.	[15]
Tolbutamide	DM02AWV	Approved	ATP-binding cassette sub-family C member 8 (ABCC8) increases the Bone marrow failure ADR of Tolbutamide.	[15]
L-leucine	DMQHN7I	Investigative	ATP-binding cassette sub-family C member 8 (ABCC8) increases the Hypoglycaemia ADR of L-leucine.

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 ATP-binding cassette sub-family C member 8 (ABCC8).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-binding cassette sub-family C member 8 (ABCC8).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of ATP-binding cassette sub-family C member 8 (ABCC8).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP-binding cassette sub-family C member 8 (ABCC8).	[13]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [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] 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.
• [4] Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest. 2000 Oct;106(7):897-906. doi: 10.1172/JCI9804.
• [5] Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes. J Clin Endocrinol Metab. 2005 Feb;90(2):789-94. doi: 10.1210/jc.2004-1604. Epub 2004 Nov 23.
• [6] The lessons of early-onset monogenic diabetes for the understanding of diabetes pathogenesis. Best Pract Res Clin Endocrinol Metab. 2012 Apr;26(2):171-87. doi: 10.1016/j.beem.2011.12.001.
• [7] Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011 Oct 3;6:63. doi: 10.1186/1750-1172-6-63.
• [8] Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia. 2012 Jan;55(1):123-7. doi: 10.1007/s00125-011-2319-x. Epub 2011 Oct 12.
• [9] Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003 Feb;33(2):177-82. doi: 10.1038/ng1071. Epub 2003 Jan 13.
• [10] 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.
• [11] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [12] 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.
• [13] 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.
• [14] Role of transporter genes in cisplatin resistance. In Vivo. 2008 May-Jun;22(3):279-83.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.