Details of Drug Off-Target (DOT)

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

• DOT Name: Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3)
• Synonyms: Solute carrier family 46 member 3
• Gene Name: SLC46A3
• Related Disease:
  Neoplasm
  Advanced cancer
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
• UniProt ID: S46A3_HUMAN
• Pfam ID: PF07690
• Sequence:
  MKILFVEPAIFLSAFAMTLTGPLTTQYVYRRIWEETGNYTFSSDSNISECEKNKSSPIFA
  FQEEVQKKVSRFNLQMDISGLIPGLVSTFILLSISDHYGRKFPMILSSVGALATSVWLCL
  LCYFAFPFQLLIASTFIGAFCGNYTTFWGACFAYIVDQCKEHKQKTIRIAIIDFLLGLVT
  GLTGLSSGYFIRELGFEWSFLIIAVSLAVNLIYILFFLGDPVKECSSQNVTMSCSEGFKN
  LFYRTYMLFKNASGKRRFLLCLLLFTVITYFFVVIGIAPIFILYELDSPLCWNEVFIGYG
  SALGSASFLTSFLGIWLFSYCMEDIHMAFIGIFTTMTGMAMTAFASTTLMMFLARVPFLF
  TIVPFSVLRSMLSKVVRSTEQGTLFACIAFLETLGGVTAVSTFNGIYSATVAWYPGFTFL
  LSAGLLLLPAISLCVVKCTSWNEGSYELLIQEESSEDASDR
• Function: Lysosomal proton-coupled steroid conjugate and bile acid transporter. Preferentially recognizes lipophilic steroid conjugates or bile acis as endogenous substrates and seems to mediate escape from lysosomes to the cytoplasm. Modulates hepatic cytosolic copper homeostasis, maybe acting as a lysosomal copper transporter and sequestering copper ions in the lysosome. Transports catabolites of non-cleavable antibody-drug conjugates from the lysosome to the cytoplasm. Delivers pathogen-associated molecular patterns to cytosolic pattern recognition receptors as part of the innate immune response to microbes. Selectively transports bacterial muramyl dipeptide (MDP) into the cytosol for recognition by NOD2, triggering inflammatory responses. Likely acts as a redundant importer of cyclic GMP-AMP dinucleotides (cGAMPs) in monocyte and macrophage cell lineages. The transport mechanism, its electrogenicity and stoichiometry remain to be elucidated (Probable).

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[9]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Lysosomal proton-coupled steroid conjugate and bile acid symporter SLC46A3 (SLC46A3).	[15]

References

• [1] HER2-Overexpressing/Amplified Breast Cancer as a Testing Ground for Antibody-Drug Conjugate Drug Development in Solid Tumors.Clin Cancer Res. 2020 Feb 15;26(4):775-786. doi: 10.1158/1078-0432.CCR-18-1976. Epub 2019 Oct 3.
• [2] Increased expression of SLC46A3 to oppose the progression of hepatocellular carcinoma and its effect on sorafenib therapy.Biomed Pharmacother. 2019 Jun;114:108864. doi: 10.1016/j.biopha.2019.108864. Epub 2019 Apr 10.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] 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.
• [13] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [14] 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.
• [15] 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.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.