Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDQT8GI)

• DOT Name: Interleukin-12 subunit alpha (IL12A)
• Synonyms: IL-12A; Cytotoxic lymphocyte maturation factor 35 kDa subunit; CLMF p35; IL-12 subunit p35; NK cell stimulatory factor chain 1; NKSF1
• Gene Name: IL12A
• UniProt ID: IL12A_HUMAN
• PDB ID: 1F45; 3HMX
• Pfam ID: PF03039
• Sequence:
  MCPARSLLLVATLVLLDHLSLARNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLE
  FYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMM
  ALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQK
  SSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
• Function: Heterodimerizes with IL12B to form the IL-12 cytokine or with EBI3/IL27B to form the IL-35 cytokine. IL-12 is primarily produced by professional antigen-presenting cells (APCs) such as B-cells and dendritic cells (DCs) as well as macrophages and granulocytes and regulates T-cell and natural killer-cell responses, induces the production of interferon-gamma (IFN-gamma), favors the differentiation of T-helper 1 (Th1) cells and is an important link between innate resistance and adaptive immunity. Mechanistically, exerts its biological effects through a receptor composed of IL12R1 and IL12R2 subunits. Binding to the receptor results in the rapid tyrosine phosphorylation of a number of cellular substrates including the JAK family kinases TYK2 and JAK2. In turn, recruited STAT4 gets phosphorylated and translocates to the nucleus where it regulates cytokine/growth factor responsive genes. As part of IL-35, plays essential roles in maintaining the immune homeostasis of the liver microenvironment and functions also as an immune-suppressive cytokine. Mediates biological events through unconventional receptors composed of IL12RB2 and gp130/IL6ST heterodimers or homodimers. Signaling requires the transcription factors STAT1 and STAT4, which form a unique heterodimer that binds to distinct DNA sites.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Toll-like receptor sig.ling pathway (hsa04620)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  C-type lectin receptor sig.ling pathway (hsa04625)
  JAK-STAT sig.ling pathway (hsa04630)
  Th1 and Th2 cell differentiation (hsa04658)
  Alcoholic liver disease (hsa04936)
  Type I diabetes mellitus (hsa04940)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
  Inflammatory bowel disease (hsa05321)
  Allograft rejection (hsa05330)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)
  Interleukin-35 Signalling (R-HSA-8984722)
  Interleukin-12 signaling (R-HSA-9020591)
  Interleukin-10 signaling (R-HSA-6783783)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Interleukin-12 subunit alpha (IL12A).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Interleukin-12 subunit alpha (IL12A).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Interleukin-12 subunit alpha (IL12A).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interleukin-12 subunit alpha (IL12A).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Interleukin-12 subunit alpha (IL12A).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interleukin-12 subunit alpha (IL12A).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interleukin-12 subunit alpha (IL12A).	[7]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Interleukin-12 subunit alpha (IL12A).	[8]
Ergotidine	DM78IME	Approved	Ergotidine decreases the expression of Interleukin-12 subunit alpha (IL12A).	[10]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the expression of Interleukin-12 subunit alpha (IL12A).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interleukin-12 subunit alpha (IL12A).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-12 subunit alpha (IL12A).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Interleukin-12 subunit alpha (IL12A).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Interleukin-12 subunit alpha (IL12A).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Interleukin-12 subunit alpha (IL12A).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Interleukin-12 subunit alpha (IL12A).	[17]
Manganese	DMKT129	Investigative	Manganese increases the expression of Interleukin-12 subunit alpha (IL12A).	[18]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid decreases the expression of Interleukin-12 subunit alpha (IL12A).	[19]
CYANATE	DM6HQDL	Investigative	CYANATE increases the expression of Interleukin-12 subunit alpha (IL12A).	[20]
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate increases the expression of Interleukin-12 subunit alpha (IL12A).	[21]
amthamine	DMBAX3P	Investigative	amthamine decreases the expression of Interleukin-12 subunit alpha (IL12A).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Isoniazid	DM5JVS3	Approved	Isoniazid increases the secretion of Interleukin-12 subunit alpha (IL12A).	[9]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] [Effects of vitamin A on the differentiation, maturation and functions of dendritic cells from cord blood]. Zhonghua Er Ke Za Zhi. 2004 May;42(5):340-3.
• [3] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [4] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [5] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] The influence of methotrexate on the gene expression of the pro-inflammatory cytokine IL-12A in the therapy of rheumatoid arthritis. Clin Exp Rheumatol. 2011 Nov-Dec;29(6):963-9. Epub 2011 Dec 22.
• [8] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [9] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [10] Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. J Clin Invest. 1998 Nov 15;102(10):1866-73. doi: 10.1172/JCI3692.
• [11] Treatment with atorvastatin alters the ratio of interleukin-12/interleukin-10 gene expression [corrected]. Eur J Clin Invest. 2003 Jan;33(1):88-91. doi: 10.1046/j.1365-2362.2003.01105.x.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [14] Hepatic co-cultures in vitro reveal suitable to detect Nrf2-mediated oxidative stress responses on the bladder carcinogen o-anisidine. Toxicol In Vitro. 2017 Apr;40:153-160.
• [15] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [16] Trichostatin A, a histone deacetylase inhibitor, down-regulates interleukin-12 transcription in SV-40-transformed lung epithelial cells. Cell Immunol. 2002 Jul-Aug;218(1-2):26-33. doi: 10.1016/s0008-8749(02)00523-3.
• [17] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.
• [18] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [19] The impact on T-regulatory cell related immune responses in rural women exposed to polycyclic aromatic hydrocarbons (PAHs) in household air pollution in Gansu, China: A pilot investigation. Environ Res. 2019 Jun;173:306-317. doi: 10.1016/j.envres.2019.03.053. Epub 2019 Mar 26.
• [20] Isocyanates induces DNA damage, apoptosis, oxidative stress, and inflammation in cultured human lymphocytes. J Biochem Mol Toxicol. 2008 Nov-Dec;22(6):429-40.
• [21] Expression and regulation of interleukin-23 subunits in human peripheral blood mononuclear cells and hematopoietic cell lines in response to various inducers. Cell Biol Int. 2004;28(10):689-97. doi: 10.1016/j.cellbi.2004.07.002.