Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVHL7OR)

• DOT Name: ATP-binding cassette sub-family C member 11 (ABCC11)
• Synonyms: EC 7.6.2.2; EC 7.6.2.3; Multidrug resistance-associated protein 8
• Gene Name: ABCC11
• UniProt ID: MRP8_HUMAN
• EC Number: 7.6.2.2; 7.6.2.3
• Pfam ID: PF00664 ; PF00005
• Sequence:
  MTRKRTYWVPNSSGGLVNRGIDIGDDMVSGLIYKTYTLQDGPWSQQERNPEAPGRAAVPP
  WGKYDAALRTMIPFRPKPRFPAPQPLDNAGLFSYLTVSWLTPLMIQSLRSRLDENTIPPL
  SVHDASDKNVQRLHRLWEEEVSRRGIEKASVLLVMLRFQRTRLIFDALLGICFCIASVLG
  PILIIPKILEYSEEQLGNVVHGVGLCFALFLSECVKSLSFSSSWIINQRTAIRFRAAVSS
  FAFEKLIQFKSVIHITSGEAISFFTGDVNYLFEGVCYGPLVLITCASLVICSISSYFIIG
  YTAFIAILCYLLVFPLAVFMTRMAVKAQHHTSEVSDQRIRVTSEVLTCIKLIKMYTWEKP
  FAKIIEDLRRKERKLLEKCGLVQSLTSITLFIIPTVATAVWVLIHTSLKLKLTASMAFSM
  LASLNLLRLSVFFVPIAVKGLTNSKSAVMRFKKFFLQESPVFYVQTLQDPSKALVFEEAT
  LSWQQTCPGIVNGALELERNGHASEGMTRPRDALGPEEEGNSLGPELHKINLVVSKGMML
  GVCGNTGSGKSSLLSAILEEMHLLEGSVGVQGSLAYVPQQAWIVSGNIRENILMGGAYDK
  ARYLQVLHCCSLNRDLELLPFGDMTEIGERGLNLSGGQKQRISLARAVYSDRQIYLLDDP
  LSAVDAHVGKHIFEECIKKTLRGKTVVLVTHQLQYLEFCGQIILLENGKICENGTHSELM
  QKKGKYAQLIQKMHKEATSDMLQDTAKIAEKPKVESQALATSLEESLNGNAVPEHQLTQE
  EEMEEGSLSWRVYHHYIQAAGGYMVSCIIFFFVVLIVFLTIFSFWWLSYWLEQGSGTNSS
  RESNGTMADLGNIADNPQLSFYQLVYGLNALLLICVGVCSSGIFTKVTRKASTALHNKLF
  NKVFRCPMSFFDTIPIGRLLNCFAGDLEQLDQLLPIFSEQFLVLSLMVIAVLLIVSVLSP
  YILLMGAIIMVICFIYYMMFKKAIGVFKRLENYSRSPLFSHILNSLQGLSSIHVYGKTED
  FISQFKRLTDAQNNYLLLFLSSTRWMALRLEIMTNLVTLAVALFVAFGISSTPYSFKVMA
  VNIVLQLASSFQATARIGLETEAQFTAVERILQYMKMCVSEAPLHMEGTSCPQGWPQHGE
  IIFQDYHMKYRDNTPTVLHGINLTIRGHEVVGIVGRTGSGKSSLGMALFRLVEPMAGRIL
  IDGVDICSIGLEDLRSKLSVIPQDPVLLSGTIRFNLDPFDRHTDQQIWDALERTFLTKAI
  SKFPKKLHTDVVENGGNFSVGERQLLCIARAVLRNSKIILIDEATASIDMETDTLIQRTI
  REAFQGCTVLVIAHRVTTVLNCDHILVMGNGKVVEFDRPEVLRKKPGSLFAALMATATSS
  LR
• Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Plays a role in physiological processes involving bile acids, conjugated steroids and cyclic nucleotides, including cAMP and cGMP. Mediates the ATP-dependent efflux of a range of physiological lipophilic anions, including the glutathione S-conjugates leukotriene C4 and dinitrophenyl S-glutathione, steroid sulfates, such as dehydroepiandrosterone 3-sulfate (DHEAS) and estrone 3-sulfate, glucuronides such as estradiol 17-beta-D-glucuronide (E(2)17betaG), the monoanionic bile acids glycocholate and taurocholate, and methotrexate. Plays a role in the transport of earwax components. Participates in the secretion of odorants and their precursors from the apocrine sweat glands, including the secretion of glutamine conjugates, as well as the Cys-Gly-(S) conjugates of 3-methyl-3-sulfanyl-hexanol. Involved in the cellular extrusion of nucleotide analogs, hence confering resistance to various drugs, including clinically relevant drugs such as 5-fluorouracil (5-FU) and methotrexate.
• Tissue Specificity: Expressed in apocrine glands (at protein level) . Expressed at moderate levels in breast and testis and at very low levels in liver, brain and placenta . Localizes to axons of the central and peripheral nervous system (at protein level) .
• KEGG Pathway: ABC transporters (hsa02010)
• Reactome Pathway: ABC-family proteins mediated transport (R-HSA-382556)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	ATP-binding cassette sub-family C member 11 (ABCC11) decreases the abundance of Methotrexate.	[10]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	ATP-binding cassette sub-family C member 11 (ABCC11) decreases the response to substance of Fluorouracil.	[2]
Pemetrexed	DMMX2E6	Approved	ATP-binding cassette sub-family C member 11 (ABCC11) decreases the response to substance of Pemetrexed.	[10]
5-Fluoro-2'-Deoxyuridine-5'-Monophosphate	DME1AGO	Investigative	ATP-binding cassette sub-family C member 11 (ABCC11) decreases the response to substance of 5-Fluoro-2'-Deoxyuridine-5'-Monophosphate.	[12]

2 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 C member 11 (ABCC11).	[1]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of ATP-binding cassette sub-family C member 11 (ABCC11).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATP-binding cassette sub-family C member 11 (ABCC11).	[2]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of ATP-binding cassette sub-family C member 11 (ABCC11).	[4]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of ATP-binding cassette sub-family C member 11 (ABCC11).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP-binding cassette sub-family C member 11 (ABCC11).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of ATP-binding cassette sub-family C member 11 (ABCC11).	[7]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of ATP-binding cassette sub-family C member 11 (ABCC11).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ATP-binding cassette sub-family C member 11 (ABCC11).	[9]

References

• [1] 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.
• [2] ABCC11 expression is regulated by estrogen in MCF7 cells, correlated with estrogen receptor alpha expression in postmenopausal breast tumors and overexpressed in tamoxifen-resistant breast cancer cells. Endocr Relat Cancer. 2008 Mar;15(1):125-38. doi: 10.1677/ERC-07-0189.
• [3] 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.
• [4] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [5] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [8] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [10] ABCC11/MRP8 confers pemetrexed resistance in lung cancer. Cancer Sci. 2010 Nov;101(11):2404-10.
• [11] ABCC11 expression is regulated by estrogen in MCF7 cells, correlated with estrogen receptor alpha expression in postmenopausal breast tumors and overexpressed in tamoxifen-resistant breast cancer cells. Endocr Relat Cancer. 2008 Mar;15(1):125-38. doi: 10.1677/ERC-07-0189.
• [12] MRP8/ABCC11 directly confers resistance to 5-fluorouracil. Mol Cancer Ther. 2007 Jan;6(1):122-7.