Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXM5JW4)

• DOT Name: Calcium/manganese antiporter SLC30A10 (SLC30A10)
• Synonyms: Solute carrier family 30 member 10; Zinc transporter 10; ZnT-10
• Gene Name: SLC30A10
• Related Disease: Cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome
• UniProt ID: ZNT10_HUMAN
• Pfam ID: PF01545
• Sequence:
  MGRYSGKTCRLLFMLVLTVAFFVAELVSGYLGNSIALLSDSFNMLSDLISLCVGLSAGYI
  ARRPTRGFSATYGYARAEVVGALSNAVFLTALCFTIFVEAVLRLARPERIDDPELVLIVG
  VLGLLVNVVGLLIFQDCAAWFACCLRGRSRRLQQRQQLAEGCVPGAFGGPQGAEDPRRAA
  DPTAPGSDSAVTLRGTSVERKREKGATVFANVAGDSFNTQNEPEDMMKKEKKSEALNIRG
  VLLHVMGDALGSVVVVITAIIFYVLPLKSEDPCNWQCYIDPSLTVLMVIIILSSAFPLIK
  ETAAILLQMVPKGVNMEELMSKLSAVPGISSVHEVHIWELVSGKIIATLHIKYPKDRGYQ
  DASTKIREIFHHAGIHNVTIQFENVDLKEPLEQKDLLLLCNSPCISKGCAKQLCCPPGAL
  PLAHVNGCAEHNGGPSLDTYGSDGLSRRDAREVAIEVSLDSCLSDHGQSLNKTQEDQCYV
  NRTHF
• Function: Calcium:manganese antiporter of the plasma membrane mediating the efflux of intracellular manganese coupled to an active extracellular calcium exchange. Required for intracellular manganese homeostasis, an essential cation for the function of several enzymes, including some crucially important for the metabolism of neurotransmitters and other neuronal metabolic pathways. Manganese can also be cytotoxic and induce oxidative stress, mitochondrial dysfunction and apoptosis. Could also have an intracellular zinc ion transporter activity, directly regulating intracellular zinc ion homeostasis and more indirectly various signaling pathway and biological processes.
• Tissue Specificity: Specifically expressed in fetal liver and fetal brain . Expressed in adult tissues with relative levels small intestine > liver > testes > brain > ovary > colon > cervix > prostate > placenta . Expressed in liver and neurons of the nervous system (at protein level) .
• Reactome Pathway: Metal ion SLC transporters (R-HSA-425410)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome	DIS2GA85	Strong	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Manganese	DMKT129	Investigative	Calcium/manganese antiporter SLC30A10 (SLC30A10) increases the abundance of Manganese.	[16]
3-iodothyronamine	DM3L0F8	Investigative	Calcium/manganese antiporter SLC30A10 (SLC30A10) affects the uptake of 3-iodothyronamine.	[17]

15 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 Calcium/manganese antiporter SLC30A10 (SLC30A10).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[10]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[14]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[6]
Edetic acid	DM10D85	Investigative	Edetic acid increases the expression of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Calcium/manganese antiporter SLC30A10 (SLC30A10).	[12]

References

• [1] 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.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol. 2016 Oct;163:77-87.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [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] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [11] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [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] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [14] 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.
• [15] Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012 Mar 9;90(3):467-77.
• [16] Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: a new treatable disorder. Mov Disord. 2012 Sep 1;27(10):1317-22. doi: 10.1002/mds.25138. Epub 2012 Aug 23.
• [17] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.