Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJBHLX0)

• DOT Name: Hydroxycarboxylic acid receptor 3 (HCAR3)
• Synonyms: G-protein coupled receptor 109B; G-protein coupled receptor HM74; G-protein coupled receptor HM74B; Niacin receptor 2; Nicotinic acid receptor 2
• Gene Name: HCAR3
• UniProt ID: HCAR3_HUMAN
• PDB ID: 8IHJ; 8IHK
• Pfam ID: PF00001
• Sequence:
  MNRHHLQDHFLEIDKKNCCVFRDDFIAKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWK
  SSRIFLFNLAVADFLLIICLPFVMDYYVRRSDWKFGDIPCRLVLFMFAMNRQGSIIFLTV
  VAVDRYFRVVHPHHALNKISNWTAAIISCLLWGITVGLTVHLLKKKLLIQNGTANVCISF
  SICHTFRWHEAMFLLEFFLPLGIILFCSARIIWSLRQRQMDRHAKIKRAITFIMVVAIVF
  VICFLPSVVVRIHIFWLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPS
  FPNFFSTLINRCLQRKITGEPDNNRSTSVELTGDPNKTRGAPEALIANSGEPWSPSYLGP
  TSNNHSKKGHCHQEPASLEKQLGCCIE
• Function: Receptor for 3-OH-octanoid acid mediates a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. Acts as a low affinity receptor for nicotinic acid. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet.
• Tissue Specificity: Expression largely restricted to adipose tissue and spleen.
• KEGG Pathway: cAMP sig.ling pathway (hsa04024)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Hydroxycarboxylic acid-binding receptors (R-HSA-3296197)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	Hydroxycarboxylic acid receptor 3 (HCAR3) decreases the abundance of [3H]cAMP.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Hydroxycarboxylic acid receptor 3 (HCAR3).	[1]

11 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 Hydroxycarboxylic acid receptor 3 (HCAR3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[6]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[7]
Vitamin B3	DMQVRZH	Approved	Vitamin B3 increases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Hydroxycarboxylic acid receptor 3 (HCAR3).	[12]

References

• [1] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [8] Structure-dependent effects of pyridine derivatives on mechanisms of intestinal fatty acid uptake: regulation of nicotinic acid receptor and fatty acid transporter expression. J Nutr Biochem. 2014 Jul;25(7):750-7. doi: 10.1016/j.jnutbio.2014.03.002. Epub 2014 Mar 22.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [11] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Aromatic D-amino acids act as chemoattractant factors for human leukocytes through a G protein-coupled receptor, GPR109B. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3930-4.