Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV41F7T)

• DOT Name: Pro-opiomelanocortin (POMC)
• Synonyms: POMC; Corticotropin-lipotropin
• Gene Name: POMC
• Related Disease:
  Inherited obesity
  Obesity due to pro-opiomelanocortin deficiency
• UniProt ID: COLI_HUMAN
• PDB ID: 4XNH; 4XPD; 4Y49; 6TUB; 7F53; 7F54; 7PIV; 8F7Q
• Pfam ID: PF00976 ; PF08384 ; PF08035
• Sequence:
  MPRSCCSRSGALLLALLLQASMEVRGWCLESSQCQDLTTESNLLECIRACKPDLSAETPM
  FPGNGDEQPLTENPRKYVMGHFRWDRFGRRNSSSSGSSGAGQKREDVSAGEDCGPLPEGG
  PEPRSDGAKPGPREGKRSYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEFKREL
  TGQRLREGDGPDGPADDGAGAQADLEHSLLVAAEKKDEGPYRMEHFRWGSPPKDKRYGGF
  MTSEKSQTPLVTLFKNAIIKNAYKKGE
• Function: [Corticotropin]: Stimulates the adrenal glands to release cortisol.; [Melanocyte-stimulating hormone alpha]: Anorexigenic peptide. Increases the pigmentation of skin by increasing melanin production in melanocytes.; [Melanocyte-stimulating hormone beta]: Increases the pigmentation of skin by increasing melanin production in melanocytes.; [Beta-endorphin]: Endogenous orexigenic opiate.; [Met-enkephalin]: Endogenous opiate.
• Tissue Specificity: ACTH and MSH are produced by the pituitary gland.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Adipocytokine sig.ling pathway (hsa04920)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
• Reactome Pathway:
  Androgen biosynthesis (R-HSA-193048)
  Glucocorticoid biosynthesis (R-HSA-194002)
  G-protein activation (R-HSA-202040)
  Peptide hormone biosynthesis (R-HSA-209952)
  Endogenous sterols (R-HSA-211976)
  Peptide ligand-binding receptors (R-HSA-375276)
  G alpha (s) signalling events (R-HSA-418555)
  G alpha (i) signalling events (R-HSA-418594)
  Defective ACTH causes obesity and POMCD (R-HSA-5579031)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes (R-HSA-9615017)
  Opioid Signalling (R-HSA-111885)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited obesity	DISVH4OT	Strong	Semidominant	[1]
Obesity due to pro-opiomelanocortin deficiency	DISM0UQF	Strong	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Pro-opiomelanocortin (POMC) increases the abundance of Progesterone.	[27]
Hydrocortisone	DMGEMB7	Approved	Pro-opiomelanocortin (POMC) increases the abundance of Hydrocortisone.	[27]
Aldosterone	DM9S2JW	Approved	Pro-opiomelanocortin (POMC) decreases the abundance of Aldosterone.	[29]
Dehydroepiandrosterone sulfate	DM4Q80H	Approved	Pro-opiomelanocortin (POMC) increases the abundance of Dehydroepiandrosterone sulfate.	[30]
Deoxycorticosterone	DMW6YLS	Investigative	Pro-opiomelanocortin (POMC) increases the abundance of Deoxycorticosterone.	[31]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenylephrine	DMZHUO5	Approved	Pro-opiomelanocortin (POMC) increases the response to substance of Phenylephrine.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pro-opiomelanocortin (POMC).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Pro-opiomelanocortin (POMC).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Pro-opiomelanocortin (POMC).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Pro-opiomelanocortin (POMC).	[6]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Pro-opiomelanocortin (POMC).	[7]
Citalopram	DM2G9AE	Approved	Citalopram increases the expression of Pro-opiomelanocortin (POMC).	[10]
Clonidine	DM6RZ9Q	Approved	Clonidine increases the expression of Pro-opiomelanocortin (POMC).	[11]
Lansoprazole	DMXYLQ3	Approved	Lansoprazole increases the expression of Pro-opiomelanocortin (POMC).	[12]
Prednisone	DM2HG4X	Approved	Prednisone decreases the expression of Pro-opiomelanocortin (POMC).	[13]
Bromocriptine	DMVE3TK	Approved	Bromocriptine increases the expression of Pro-opiomelanocortin (POMC).	[14]
Fentanyl	DM8WAHT	Approved	Fentanyl decreases the expression of Pro-opiomelanocortin (POMC).	[15]
Naloxone	DM3FXMA	Approved	Naloxone increases the expression of Pro-opiomelanocortin (POMC).	[16]
Metyrapone	DMI7FVQ	Approved	Metyrapone increases the expression of Pro-opiomelanocortin (POMC).	[17]
Buspirone	DMBS632	Approved	Buspirone increases the expression of Pro-opiomelanocortin (POMC).	[20]
Sumatriptan	DMVYXR8	Approved	Sumatriptan decreases the expression of Pro-opiomelanocortin (POMC).	[21]
Pentagastrin	DMRCLZB	Approved	Pentagastrin increases the expression of Pro-opiomelanocortin (POMC).	[22]
Sufentanil	DMU7YEL	Approved	Sufentanil decreases the expression of Pro-opiomelanocortin (POMC).	[23]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Pro-opiomelanocortin (POMC).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Pro-opiomelanocortin (POMC).	[24]

4 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cocaine	DMSOX7I	Approved	Cocaine increases the secretion of Pro-opiomelanocortin (POMC).	[8]
Melatonin	DMKWFBT	Approved	Melatonin decreases the response to substance of Pro-opiomelanocortin (POMC).	[9]
Triamcinolone	DM98IXF	Approved	Triamcinolone decreases the response to substance of Pro-opiomelanocortin (POMC).	[18]
Cyproheptadine	DM92AH3	Approved	Cyproheptadine decreases the secretion of Pro-opiomelanocortin (POMC).	[19]

2 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 Pro-opiomelanocortin (POMC).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pro-opiomelanocortin (POMC).	[26]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] Analgesic action of acetaminophen in symptomatic osteoarthritis of the knee. Rheumatology (Oxford). 2006 Jun;45(6):765-70. doi: 10.1093/rheumatology/kei253. Epub 2006 Jan 31.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Male pseudohermaphroditism with hypertension due to a 17alpha-hydroxylation deficiency. Clin Endocrinol (Oxf). 1976 Jan;5(1):53-61.
• [7] The role of acetaldehyde in mediating effects of alcohol on expression of endogenous opioid system genes in a neuroblastoma cell line. FASEB J. 2008 Mar;22(3):662-70. doi: 10.1096/fj.07-8346com. Epub 2007 Oct 12.
• [8] Temporal concordance of cocaine effects on mood states and neuroendocrine hormones. Psychoneuroendocrinology. 2002 Jan-Feb;27(1-2):71-82. doi: 10.1016/s0306-4530(01)00036-1.
• [9] [Melatonin reduces cortisol response to ACTH in humans]. Rev Med Chil. 2008 Nov;136(11):1390-7. doi: 10.4067/s0034-98872008001100004.
• [10] Neuroendocrine effects of citalopram, a selective serotonin re-uptake inhibitor, during lifespan in humans. J Endocrinol Invest. 2010 Oct;33(9):657-62. doi: 10.1007/BF03346666. Epub 2010 Apr 22.
• [11] Normalization of blood pressure and plasma concentrations of beta-endorphin and leucine-enkephalin in patients with primary hypertension after treatment with clonidine. J Cardiovasc Pharmacol. 1987;10 Suppl 12:S147-51.
• [12] Comparison of the effects of proton pump inhibitors on human plasma adrenocorticotropic hormone and cortisol levels under the starved condition. Biomed Pharmacother. 2006 Apr;60(3):109-12. doi: 10.1016/j.biopha.2006.01.004. Epub 2006 Feb 21.
• [13] Prednisone effects on neurochemistry and behavior. Preliminary findings. Arch Gen Psychiatry. 1990 Oct;47(10):963-8. doi: 10.1001/archpsyc.1990.01810220079010.
• [14] Bromocriptine inhibits pro-opiomelanocortin mRNA and ACTH precursor secretion in small cell lung cancer cell lines. J Clin Invest. 1992 Sep;90(3):705-10. doi: 10.1172/JCI115941.
• [15] Serum beta-endorphin response to stress before and after operation under fentanyl anesthesia in neonates, infants and preschool children. Eur J Pediatr Surg. 2010 Mar;20(2):106-10. doi: 10.1055/s-0029-1243620. Epub 2010 Jan 18.
• [16] Endogenous opioids modulate the cardiovascular response to mental stress. Psychoneuroendocrinology. 1990;15(3):185-92. doi: 10.1016/0306-4530(90)90029-9.
• [17] Mineralocorticoid receptor function in posttraumatic stress disorder after pretreatment with metyrapone. Biol Psychiatry. 2006 Oct 1;60(7):784-7. doi: 10.1016/j.biopsych.2006.01.014. Epub 2006 Mar 29.
• [18] Steroid myopathy induced by epidural triamcinolone injection. Br J Rheumatol. 1995 Apr;34(4):385-6. doi: 10.1093/rheumatology/34.4.385.
• [19] [Toxicity of cyproheptadine. Side effects and accidental overdosage (author's transl)]. Monatsschr Kinderheilkd (1902). 1978 Mar;126(3):123-6.
• [20] Hormonal responses to the 5-HT1A agonist buspirone in remitted endogenous depressive patients after long-term imipramine treatment. Psychoneuroendocrinology. 2010 May;35(4):481-9. doi: 10.1016/j.psyneuen.2009.08.012. Epub 2009 Sep 16.
• [21] The effects of oral sumatriptan, a 5-HT1 receptor agonist, on circulating ACTH and cortisol concentrations in man. Br J Clin Pharmacol. 1995 Apr;39(4):389-95. doi: 10.1111/j.1365-2125.1995.tb04467.x.
• [22] Dose response of adrenocorticotropin and cortisol to the CCK-B agonist pentagastrin. Neuropsychopharmacology. 1999 Oct;21(4):485-94. doi: 10.1016/S0893-133X(98)00124-9.
• [23] Withdrawal following sufentanil/propofol and sufentanil/midazolam. Sedation in surgical ICU patients: correlation with central nervous parameters and endogenous opioids. Intensive Care Med. 2005 Mar;31(3):380-7. doi: 10.1007/s00134-005-2579-3. Epub 2005 Feb 16.
• [24] Examining the genomic influence of skin antioxidants in vitro. Mediators Inflamm. 2010;2010.
• [25] 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.
• [26] 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.
• [27] Melatonin exerts direct inhibitory actions on ACTH responses in the human adrenal gland. Horm Metab Res. 2011 May;43(5):337-42. doi: 10.1055/s-0031-1271693. Epub 2011 Feb 17.
• [28] Effect of sodium depletion on pressor responsiveness in ACTH-induced hypertension in man. Clin Exp Pharmacol Physiol. 1987 Mar;14(3):237-42. doi: 10.1111/j.1440-1681.1987.tb00382.x.
• [29] Hormonal background of the hypertension and fluid derangements associated with adrenocorticotrophic hormone treatment of infants. Eur J Pediatr. 1989 Aug;148(8):737-41. doi: 10.1007/BF00443098.
• [30] Maintenance of cell proliferation and steroidogenesis in cultured human fetal adrenal cells chronically exposed to adrenocorticotropic hormone: rationalization of in vitro and in vivo findings. Biol Reprod. 1990 Apr;42(4):683-91. doi: 10.1095/biolreprod42.4.683.
• [31] Dexamethasone-suppressible hyperaldosteronism. Adrenal transition cell hyperplasia?. Hypertension. 1986 Aug;8(8):669-76. doi: 10.1161/01.hyp.8.8.669.