Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD721UF)

• DOT Name: Parathyroid hormone (PTH)
• Synonyms: PTH; Parathormone; Parathyrin
• Gene Name: PTH
• Related Disease:
  Hypoparathyroidism, familial isolated 1
  Familial isolated hypoparathyroidism due to impaired PTH secretion
• UniProt ID: PTHY_HUMAN
• PDB ID: 1BWX; 1ET1; 1FVY; 1HPH; 1HPY; 1HTH; 1ZWA; 1ZWB; 1ZWD; 1ZWE; 1ZWF; 1ZWG; 2L1X; 3C4M; 7VVK; 7VVL; 7VVM; 7VVN; 7VVO; 7Y36; 8FLQ; 8HA0; 8HAO
• Pfam ID: PF01279
• Sequence:
  MIPAKDMAKVMIVMLAICFLTKSDGKSVKKRSVSEIQLMHNLGKHLNSMERVEWLRKKLQ
  DVHNFVALGAPLAPRDAGSQRPRKKEDNVLVESHEKSLGEADKADVNVLTKAKSQ
• Function: PTH elevates calcium level by dissolving the salts in bone and preventing their renal excretion. Stimulates [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblastic cells.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Rheumatoid arthritis (hsa05323)
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypoparathyroidism, familial isolated 1	DISJJOWA	Strong	Autosomal recessive	[1]
Familial isolated hypoparathyroidism due to impaired PTH secretion	DISASHAN	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Parathyroid hormone (PTH) increases the Bone density decreased ADR of Ciclosporin.	[15]
Cimetidine	DMH61ZB	Approved	Parathyroid hormone (PTH) increases the Hyperparathyroidism secondary ADR of Cimetidine.	[15]

10 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 (PTH).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Parathyroid hormone (PTH).	[5]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Parathyroid hormone (PTH).	[6]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol decreases the expression of Parathyroid hormone (PTH).	[7]
Phosphate	DMUXQG7	Approved	Phosphate increases the expression of Parathyroid hormone (PTH).	[8]
Paricalcitol	DMYBV3G	Approved	Paricalcitol decreases the expression of Parathyroid hormone (PTH).	[9]
Cinacalcet	DMCX0K3	Approved	Cinacalcet decreases the expression of Parathyroid hormone (PTH).	[10]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Parathyroid hormone (PTH).	[11]
Lithium	DMZ3OU6	Phase 2	Lithium increases the expression of Parathyroid hormone (PTH).	[12]
Terfenadine	DM4KLPT	Withdrawn from market	Terfenadine decreases the expression of Parathyroid hormone (PTH).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Parathyroid hormone (PTH).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Parathyroid hormone (PTH).	[13]

References

• [1] A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. Nat Genet. 1992 May;1(2):149-52. doi: 10.1038/ng0592-149.
• [2] Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest. 1990 Oct;86(4):1084-7. doi: 10.1172/JCI114811.
• [3] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [4] 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.
• [5] Comparison of intermittent and continuous oral administration of calcitriol in dialysis patients: a randomized prospective trial. Nephron. 1994;67(1):48-53. doi: 10.1159/000187887.
• [6] Phenytoin induced vitamin D deficiency presenting as proximal muscle weakness. Indian Pediatr. 2010 Jul;47(7):624-5. doi: 10.1007/s13312-010-0121-3.
• [7] Safety and T cell modulating effects of high dose vitamin D3 supplementation in multiple sclerosis. PLoS One. 2010 Dec 13;5(12):e15235. doi: 10.1371/journal.pone.0015235.
• [8] Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol. 2008 May;3(3):658-64. doi: 10.2215/CJN.04981107. Epub 2008 Feb 6.
• [9] Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int. 2003 Apr;63(4):1483-90. doi: 10.1046/j.1523-1755.2003.00878.x.
• [10] Normalization of lithium-induced hypercalcemia and hyperparathyroidism with cinacalcet hydrochloride. Am J Kidney Dis. 2006 Nov;48(5):832-7. doi: 10.1053/j.ajkd.2006.07.019.
• [11] A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer. Br J Cancer. 1998 Jul;78(1):6-13. doi: 10.1038/bjc.1998.434.
• [12] Lithium therapy, hypercalcemia, and hyperparathyroidism. Am J Ther. 1997 Sep-Oct;4(9-10):323-5. doi: 10.1097/00045391-199709000-00007.
• [13] 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.
• [14] Osteoporosis, teriparatide, and dosing of calcium and vitamin D. N Engl J Med. 2005 May 5;352(18):1930-1. doi: 10.1056/NEJM200505053521822.
• [15] 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.