Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQF5ZAK)

• DOT Name: Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R)
• Synonyms: PTH/PTHrP type I receptor; PTH/PTHr receptor; Parathyroid hormone 1 receptor; PTH1 receptor
• Gene Name: PTH1R
• Related Disease:
  Chondrodysplasia Blomstrand type
  Metaphyseal chondrodysplasia, Jansen type
  Primary failure of tooth eruption
  Eiken syndrome
• UniProt ID: PTH1R_HUMAN
• PDB ID: 1BL1; 3C4M; 3H3G; 3L2J; 4Z8J; 5EMB; 6NBF; 6NBH; 6NBI; 7UZO; 7UZP; 7VVJ; 7VVK; 7VVL; 7VVM; 7VVN; 7VVO; 7Y35; 7Y36; 8BIA; 8BJ0; 8D51; 8D52; 8FLQ; 8FLR; 8FLS; 8FLT; 8FLU; 8GW8; 8HA0; 8HAF; 8HAO; 8JR9
• Pfam ID: PF00002 ; PF02793
• Sequence:
  MGTARIAPGLALLLCCPVLSSAYALVDADDVMTKEEQIFLLHRAQAQCEKRLKEVLQRPA
  SIMESDKGWTSASTSGKPRKDKASGKLYPESEEDKEAPTGSRYRGRPCLPEWDHILCWPL
  GAPGEVVAVPCPDYIYDFNHKGHAYRRCDRNGSWELVPGHNRTWANYSECVKFLTNETRE
  REVFDRLGMIYTVGYSVSLASLTVAVLILAYFRRLHCTRNYIHMHLFLSFMLRAVSIFVK
  DAVLYSGATLDEAERLTEEELRAIAQAPPPPATAAAGYAGCRVAVTFFLYFLATNYYWIL
  VEGLYLHSLIFMAFFSEKKYLWGFTVFGWGLPAVFVAVWVSVRATLANTGCWDLSSGNKK
  WIIQVPILASIVLNFILFINIVRVLATKLRETNAGRCDTRQQYRKLLKSTLVLMPLFGVH
  YIVFMATPYTEVSGTLWQVQMHYEMLFNSFQGFFVAIIYCFCNGEVQAEIKKSWSRWTLA
  LDFKRKARSGSSSYSYGPMVSHTSVTNVGPRVGLGLPLSPRLLPTATTNGHPQLPGHAKP
  GTPALETLETTPPAMAAPKDDGFLNGSCSGLDEEASGPERPPALLQEEWETVM
• Function: Receptor for parathyroid hormone and for parathyroid hormone-related peptide. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system.
• Tissue Specificity: Expressed in most tissues. Most abundant in kidney, bone and liver.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Class B/2 (Secretin family receptors) (R-HSA-373080)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chondrodysplasia Blomstrand type	DISVSUWV	Definitive	Autosomal recessive	[1]
Metaphyseal chondrodysplasia, Jansen type	DIS5WUHF	Definitive	Autosomal dominant	[2]
Primary failure of tooth eruption	DISL016F	Definitive	Autosomal dominant	[3]
Eiken syndrome	DIS4J3C3	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 7 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) increases the Electrolyte imbalance ADR of Doxorubicin.	[12]
Cisplatin	DMRHGI9	Approved	Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) increases the Electrolyte imbalance ADR of Cisplatin.	[12]
Ethanol	DMDRQZU	Approved	Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) increases the Hyperparathyroidism ADR of Ethanol.	[12]
Furosemide	DMMQ8ZG	Approved	Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) increases the Hyperparathyroidism ADR of Furosemide.	[12]
Urea	DMUK75B	Approved	Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) increases the Renal failure chronic ADR of Urea.	[12]
Paricalcitol	DMYBV3G	Approved	Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) increases the Iron and trace metal metabolism disorders ADR of Paricalcitol.	[12]
Acetazolamide	DM1AF5U	Approved	Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) increases the Acidosis ADR of Acetazolamide.	[12]

3 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 Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R).	[10]

References

• [1] Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Hum Mol Genet. 2005 Jan 1;14(1):1-5. doi: 10.1093/hmg/ddi001. Epub 2004 Nov 3.
• [2] Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med. 1996 Sep 5;335(10):708-14. doi: 10.1056/NEJM199609053351004.
• [3] PTHR1 loss-of-function mutations in familial, nonsyndromic primary failure of tooth eruption. Am J Hum Genet. 2008 Dec;83(6):781-6. doi: 10.1016/j.ajhg.2008.11.006.
• [4] 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.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] 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.
• [12] 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.