Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTVLG21)

• DTT Name: Multidrug resistance protein 3
• Synonyms: ATP-binding cassette sub-family C member 3; Canalicular multispecific organic anion transporter 2; MOAT-D; Multi-specific organic anion transporter D; Multidrug resistance-associated protein 3
• Gene Name: ABCC3
• BioChemical Class: Single Protein
• UniProt ID: MRP3_HUMAN
• TTD ID: TE0012
• Sequence:
  MDALCGSGELGSKFWDSNLSVHTENPDLTPCFQNSLLAWVPCIYLWVALPCYLLYLRHHC
  RGYIILSHLSKLKMVLGVLLWCVSWADLFYSFHGLVHGRAPAPVFFVTPLVVGVTMLLAT
  LLIQYERLQGVQSSGVLIIFWFLCVVCAIVPFRSKILLAKAEGEISDPFRFTTFYIHFAL
  VLSALILACFREKPPFFSAKNVDPNPYPETSAGFLSRLFFWWFTKMAIYGYRHPLEEKDL
  WSLKEEDRSQMVVQQLLEAWRKQEKQTARHKASAAPGKNASGEDEVLLGARPRPRKPSFL
  KALLATFGSSFLISACFKLIQDLLSFINPQLLSILIRFISNPMAPSWWGFLVAGLMFLCS
  MMQSLILQHYYHYIFVTGVKFRTGIMGVIYRKALVITNSVKRASTVGEIVNLMSVDAQRF
  MDLAPFLNLLWSAPLQIILAIYFLWQNLGPSVLAGVAFMVLLIPLNGAVAVKMRAFQVKQ
  MKLKDSRIKLMSEILNGIKVLKLYAWEPSFLKQVEGIRQGELQLLRTAAYLHTTTTFTWM
  CSPFLVTLITLWVYVYVDPNNVLDAEKAFVSVSLFNILRLPLNMLPQLISNLTQASVSLK
  RIQQFLSQEELDPQSVERKTISPGYAITIHSGTFTWAQDLPPTLHSLDIQVPKGALVAVV
  GPVGCGKSSLVSALLGEMEKLEGKVHMKGSVAYVPQQAWIQNCTLQENVLFGKALNPKRY
  QQTLEACALLADLEMLPGGDQTEIGEKGINLSGGQRQRVSLARAVYSDADIFLLDDPLSA
  VDSHVAKHIFDHVIGPEGVLAGKTRVLVTHGISFLPQTDFIIVLADGQVSEMGPYPALLQ
  RNGSFANFLCNYAPDEDQGHLEDSWTALEGAEDKEALLIEDTLSNHTDLTDNDPVTYVVQ
  KQFMRQLSALSSDGEGQGRPVPRRHLGPSEKVQVTEAKADGALTQEEKAAIGTVELSVFW
  DYAKAVGLCTTLAICLLYVGQSAAAIGANVWLSAWTNDAMADSRQNNTSLRLGVYAALGI
  LQGFLVMLAAMAMAAGGIQAARVLHQALLHNKIRSPQSFFDTTPSGRILNCFSKDIYVVD
  EVLAPVILMLLNSFFNAISTLVVIMASTPLFTVVILPLAVLYTLVQRFYAATSRQLKRLE
  SVSRSPIYSHFSETVTGASVIRAYNRSRDFEIISDTKVDANQRSCYPYIISNRWLSIGVE
  FVGNCVVLFAALFAVIGRSSLNPGLVGLSVSYSLQVTFALNWMIRMMSDLESNIVAVERV
  KEYSKTETEAPWVVEGSRPPEGWPPRGEVEFRNYSVRYRPGLDLVLRDLSLHVHGGEKVG
  IVGRTGAGKSSMTLCLFRILEAAKGEIRIDGLNVADIGLHDLRSQLTIIPQDPILFSGTL
  RMNLDPFGSYSEEDIWWALELSHLHTFVSSQPAGLDFQCSEGGENLSVGQRQLVCLARAL
  LRKSRILVLDEATAAIDLETDNLIQATIRTQFDTCTVLTIAHRLNTIMDYTRVLVLDKGV
  VAEFDSPANLIAARGIFYGMARDAGLA
• Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that bind and hydrolyze ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports glucuronide conjugates such as bilirubin diglucuronide, estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4). Transports also various bile salts (taurocholate, glycocholate, taurochenodeoxycholate-3-sulfate, taurolithocholate- 3-sulfate).

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Multidrug resistance-associated protein 3 (ABCC3) DTP Info
• Gene Name: ABCC3

16 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cefadroxil	DMMC345	Bacterial infection	1A00-1C4Z	Approved	[1]
Dehydroepiandrosterone sulfate	DM4Q80H	N. A.	N. A.	Approved	[2]
Efavirenz	DMC0GSJ	Human immunodeficiency virus infection	1C62	Approved	[3]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[4]
Etravirine	DMGV8QU	Human immunodeficiency virus-1 infection	1C62	Approved	[5]
Ezetimibe	DM7A8TW	Atherosclerosis	BD40	Approved	[6]
Fexofenadine	DM17ONX	Allergic rhinitis	CA08.0	Approved	[7]
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[8]
Folic Acid	DMEMBJC	Colorectal carcinoma		Approved	[9]
Glibenclamide	DM8JXPZ	Diabetic complication	5A2Y	Approved	[10]
Leucovorin	DMUAZWG	Colon adenocarcinoma		Approved	[9]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[11]
Morphine	DMRMS0L	Advanced cancer	2A00-2F9Z	Approved	[12]
Paclitaxel	DMLB81S	Breast carcinoma		Approved	[13]
Technetium (99MTC) mebrofenin	DMUEWM3	N. A.	N. A.	Approved	[14]
Teniposide	DMLW57T	Acute lymphoblastic leukaemia	2A85	Approved	[15]

5 Clinical Trial Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GLYCYRRHIZIN	DM8M2N3	Influenza virus infection	1E30-1E32	Phase 3	[16]
Cholyl lysyl fluorescein	DMALN2M	N. A.	N. A.	Phase 2	[17]
Glutathione-S-S-glutathione	DMJ85FS	N. A.	N. A.	Phase 2	[18]
Sodium taurocholate	DM3GO0J	Type-2 diabetes	5A11	Phase 1/2	[19]
Taurocholic Acid	DM2LZ8F	Type-2 diabetes	5A11	Phase 1/2	[19]

3 Preclinical Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Epipodophyllotoxins	DMVNR20	N. A.	N. A.	Preclinical	[15]
Monomethyl-auristatin-E	DMG2UJS	N. A.	N. A.	Preclinical	[13]
Scutellarin	DMJT1E5	N. A.	N. A.	Preclinical	[20]

2 Investigative Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
glycocholic acid	DM0SXNM	Discovery agent	N.A.	Investigative	[21]
[3H]estradiol-17beta-glucuronide	DM3KJ45	Discovery agent	N.A.	Investigative	[19]

References

• [1] Oral availability of cefadroxil depends on ABCC3 and ABCC4. Drug Metab Dispos. 2012 Mar;40(3):515-21.
• [2] Integration of hepatic drug transporters and phase II metabolizing enzymes: mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur J Pharm Sci. 2006 Apr;27(5):447-86.
• [3] Induction of multiple drug transporters by efavirenz. J Pharmacol Sci. 2009 Feb;109(2):242-50.
• [4] Functional reconstitution of human ABCC3 into proteoliposomes reveals a transport mechanism with positive cooperativity. Biochemistry. 2009 May 26;48(20):4423-30.
• [5] Interaction potential of etravirine with drug transporters assessed in vitro. Antimicrob Agents Chemother. 2011 Mar;55(3):1282-4.
• [6] Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009 Aug;37(8):1698-702.
• [7] Involvement of multiple efflux transporters in hepatic disposition of fexofenadine. Mol Pharmacol. 2008 May;73(5):1474-83.
• [8] ATP-binding cassette C transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Pancreatology. 2009;9(1-2):136-44.
• [9] Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32.
• [10] Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102.
• [11] Multidrug resistance protein (MRP) 1 and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)prostaglandin J2 in MCF7 breast cancer cells. Biochemistry. 2003 May 13;42(18):5429-37.
• [12] Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007 Feb;453(5):661-73.
• [13] Functional genomics identifies ABCC3 as a mediator of taxane resistance in HER2-amplified breast cancer. Cancer Res. 2008 Jul 1;68(13):5380-9.
• [14] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [15] Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001 Dec 7;276(49):46400-7.
• [16] The combination of glycyrrhizin and lamivudine can reverse the cisplatin resistance in hepatocellular carcinoma cells through inhibition of multidrug resistance-associated proteins. Int J Oncol. 2007 Dec;31(6):1465-72.
• [17] The emerging role of transport systems in liver function tests. Eur J Pharmacol. 2012 Jan 30;675(1-3):1-5.
• [18] MRP2 and 3 in health and disease. Cancer Lett. 2006 Mar 8;234(1):51-61.
• [19] Characterization of the role of polar amino acid residues within predicted transmembrane helix 17 in determining the substrate specificity of multidrug resistance protein 3. Biochemistry. 2003 Aug 26;42(33):9989-10000.
• [20] Mechanistic studies on the absorption and disposition of scutellarin in humans: selective OATP2B1-mediated hepatic uptake is a likely key determinant for its unique pharmacokinetic characteristics. Drug Metab Dispos. 2012 Oct;40(10):2009-20.
• [21] Measurement of transport activities of bile acids in human multidrug resistance-associated protein 3 using liquid chromatography-tandem mass spectrometry. Anal Sci. 2010;26(3):317-23.