Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3MLOO)

• DOT Name: Secretin (SCT)
• Gene Name: SCT
• UniProt ID: SECR_HUMAN
• PDB ID: 6WI9; 6WZG; 7D3S
• Pfam ID: PF00123
• Sequence:
  MAPRPLLLLLLLLGGSAARPAPPRARRHSDGTFTSELSRLREGARLQRLLQGLVGKRSEQ
  DAENSMAWTRLSAGLLCPSGSNMPILQAWMPLDGTWSPWLPPGPMVSEPAGAAAEGTLRP
  R
• Function: Hormone involved in different processes, such as regulation of the pH of the duodenal content, food intake and water homeostasis. Exerts its biological effects by binding to secretin receptor (SCTR), a G-protein coupled receptor expressed in the basolateral domain of several cells. Acts as a key gastrointestinal hormone by regulating the pH of the duodenal content. Secreted by S cells of the duodenum in the crypts of Lieberkuehn and regulates the pH of the duodenum by (1) inhibiting the secretion of gastric acid from the parietal cells of the stomach and (2) stimulating the production of bicarbonate (NaHCO(3)) from the ductal cells of the pancreas. Production of bicarbonate is essential to neutralize the pH and ensure no damage is done to the small intestine by the gastric acid. In addition to regulating the pH of the duodenal content, plays a central role in diet induced thermogenesis: acts as a non-sympathetic brown fat (BAT) activator mediating prandial thermogenesis, which consequentially induces satiation (Probable). Mechanistically, secretin released by the gut after a meal binds to secretin receptor (SCTR) in brown adipocytes, activating brown fat thermogenesis by stimulating lipolysis, which is sensed in the brain and promotes satiation. Also able to stimulate lipolysis in white adipocytes. Also plays an important role in cellular osmoregulation: released into the systemic circulation in response to hyperosmolality and acts at different levels in the hypothalamus, pituitary and kidney to regulate water homeostasis. Also plays a role in the central nervous system, possibly by acting as a neuropeptide hormone: required for hippocampal synaptic function and neural progenitor cells maintenance.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Pancreatic secretion (hsa04972)
  Bile secretion (hsa04976)
• Reactome Pathway:
  Glucagon-type ligand receptors (R-HSA-420092)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dopamine	DMPGUCF	Approved	Secretin (SCT) increases the metabolism of Dopamine.	[10]
AMG 386	DMQJXL4	Phase 3	Secretin (SCT) decreases the transport of AMG 386.	[12]
Chloride	DM1TJXA	Phase 3	Secretin (SCT) decreases the transport of Chloride.	[12]
Homovanillic acid	DM0SHPY	Investigative	Secretin (SCT) increases the abundance of Homovanillic acid.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Pentagastrin	DMRCLZB	Approved	Secretin (SCT) decreases the activity of Pentagastrin.	[11]

1 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 Secretin (SCT).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Secretin (SCT).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Secretin (SCT).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Secretin (SCT).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Secretin (SCT).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Secretin (SCT).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Secretin (SCT).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Secretin (SCT).	[8]
H-89	DM4RVGO	Investigative	H-89 decreases the activity of Secretin (SCT).	[9]
NPPB	DMFIWAN	Investigative	NPPB decreases the activity of Secretin (SCT).	[9]
Benzamil	DM57SVW	Investigative	Benzamil decreases the activity of Secretin (SCT).	[9]

References

• [1] 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.
• [2] Retinoic acid-induced human secretin gene expression in neuronal cells is mediated by cyclin-dependent kinase 1. Ann N Y Acad Sci. 2006 Jul;1070:393-8. doi: 10.1196/annals.1317.051.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.
• [9] Activation of transepithelial ion transport by secretin in human intestinal Caco-2 cells. Jpn J Physiol. 2000 Apr;50(2):215-25. doi: 10.2170/jjphysiol.50.215.
• [10] Administration of secretin for autism alters dopamine metabolism in the central nervous system. Brain Dev. 2006 Mar;28(2):99-103. doi: 10.1016/j.braindev.2005.05.005. Epub 2005 Sep 15.
• [11] Secretin inhibits canine gastric acid secretion in response to pentagastrin by modulating gastric histamine release. J Pharmacol Exp Ther. 1996 Nov;279(2):718-23.
• [12] The influence of secretin on ion transport in the human jejunum. Gut. 1973 Jun;14(6):485-90. doi: 10.1136/gut.14.6.485.