Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSJ12W6)

• DOT Name: Aryl hydrocarbon receptor repressor (AHRR)
• Synonyms: AhR repressor; AhRR; Class E basic helix-loop-helix protein 77; bHLHe77
• Gene Name: AHRR
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Lung cancer
  Lung carcinoma
  Adult lymphoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Colon cancer
  Colon carcinoma
  Leukemia
  Lung neoplasm
  Lymphoma
  Male infertility
  Malignant soft tissue neoplasm
  Multiple sclerosis
  Neoplasm
  Obesity
  Oral cancer
  Pediatric lymphoma
  Sarcoma
  Pulmonary disease
  Chronic kidney disease
  Endometriosis
  Gastric cancer
  Stomach cancer
  Type-1/2 diabetes
• UniProt ID: AHRR_HUMAN
• PDB ID: 5Y7Y
• Pfam ID: PF00010 ; PF00989
• Sequence:
  MPRTMIPPGECTYAGRKRRRPLQKQRPAVGAEKSNPSKRHRDRLNAELDHLASLLPFPPD
  IISKLDKLSVLRLSVSYLRVKSFFQVVQEQSSRQPAAGAPSPGDSCPLAGSAVLEGRLLL
  ESLNGFALVVSAEGTIFYASATIVDYLGFHQTDVMHQNIYDYIHVDDRQDFCRQLHWAMD
  PPQVVFGQPPPLETGDDAILGRLLRAQEWGTGTPTEYSAFLTRCFICRVRCLLDSTSGFL
  TMQFQGKLKFLFGQKKKAPSGAMLPPRLSLFCIAAPVLLPSAAEMKMRSALLRAKPRADT
  AATADAKVKATTSLCESELHGKPNYSAGRSSRESGVLVLREQTDAGRWAQVPARAPCLCL
  RGGPDLVLDPKGGSGDREEEQHRMLSRASGVTGRRETPGPTKPLPWTAGKHSEDGARPRL
  QPSKNDPPSLRPMPRGSCLPCPCVQGTFRNSPISHPPSPSPSAYSSRTSRPMRDVGEDQV
  HPPLCHFPQRSLQHQLPQPGAQRFATRGYPMEDMKLQGVPMPPGDLCGPTLLLDVSIKME
  KDSGCEGAADGCVPSQVWLGASDRSHPATFPTRMHLKTEPDSRQQVYISHLGHGVRGAQP
  HGRATAGRSRELTPFHPAHCACLEPTDGLPQSEPPHQLCARGRGEQSCTCRAAEAAPVVK
  REPLDSPQWATHSQGMVPGMLPKSALATLVPPQASGCTFLP
• Function: Mediates dioxin toxicity and is involved in regulation of cell growth and differentiation. Represses the transcription activity of AHR by competing with this transcription factor for heterodimer formation with the ARNT and subsequently binding to the xenobiotic response element (XRE) sequence present in the promoter regulatory region of variety of genes. Represses CYP1A1 by binding the XRE sequence and recruiting ANKRA2, HDAC4 and/or HDAC5. Autoregulates its expression by associating with its own XRE site.
• Tissue Specificity: Highly expressed in testis, lung, ovary, spleen and pancreas. Highly expressed in mononuclear cells (MNCs) from umbilical cord blood. Isoform 3 is highly expressed in lung, kidney, spleen and thymus. Down-regulated malignant tissue from different anatomical origins, including colon, breast, lung, stomach, cervix, and ovary.
• Reactome Pathway:
  Phase I - Functionalization of compounds (R-HSA-211945)
  Endogenous sterols (R-HSA-211976)
  Xenobiotics (R-HSA-211981)
  Aryl hydrocarbon receptor signalling (R-HSA-8937144)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Genetic Variation	[1]
Atherosclerosis	DISMN9J3	Definitive	Genetic Variation	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[2]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[2]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Leukemia	DISNAKFL	Strong	Biomarker	[9]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[10]
Lymphoma	DISN6V4S	Strong	Biomarker	[3]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[11]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[9]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Obesity	DIS47Y1K	Strong	Posttranslational Modification	[14]
Oral cancer	DISLD42D	Strong	Genetic Variation	[4]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[3]
Sarcoma	DISZDG3U	Strong	Biomarker	[9]
Pulmonary disease	DIS6060I	moderate	Genetic Variation	[1]
Chronic kidney disease	DISW82R7	Limited	Altered Expression	[15]
Endometriosis	DISX1AG8	Limited	Biomarker	[16]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[17]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[17]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	Aryl hydrocarbon receptor repressor (AHRR) affects the response to substance of 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Aryl hydrocarbon receptor repressor (AHRR).	[19]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Aryl hydrocarbon receptor repressor (AHRR).	[21]
Cotinine	DMCEZ1B	Approved	Cotinine affects the methylation of Aryl hydrocarbon receptor repressor (AHRR).	[27]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Aryl hydrocarbon receptor repressor (AHRR).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Aryl hydrocarbon receptor repressor (AHRR).	[24]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[25]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[26]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[22]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[30]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid decreases the expression of Aryl hydrocarbon receptor repressor (AHRR).	[31]

References

• [1] Novel DNA methylation sites associated with cigarette smoking among African Americans.Epigenetics. 2019 Apr;14(4):383-391. doi: 10.1080/15592294.2019.1588683. Epub 2019 Mar 27.
• [2] AHRR (cg05575921) methylation extent of leukocyte DNA and lung cancer survival.PLoS One. 2019 Feb 7;14(2):e0211745. doi: 10.1371/journal.pone.0211745. eCollection 2019.
• [3] The clastogenicity of 4NQO is cell-type dependent and linked to cytotoxicity, length of exposure and p53 proficiency.Mutagenesis. 2016 Mar;31(2):171-80. doi: 10.1093/mutage/gev069. Epub 2015 Sep 11.
• [4] Frequency of the functionally relevant aryl hydrocarbon receptor repressor (AhRR) Pro185Ala SNP in Papua New Guinea.Drug Metab Pharmacokinet. 2013;28(6):519-21. doi: 10.2133/dmpk.dmpk-13-sc-035. Epub 2013 May 7.
• [5] Suppressive effect of aryl hydrocarbon receptor repressor on transcriptional activity of estrogen receptor alpha by protein-protein interaction in stably and transiently expressing cell lines.Mol Cell Endocrinol. 2008 Sep 10;291(1-2):87-94. doi: 10.1016/j.mce.2008.05.004. Epub 2008 May 14.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] Filaggrin variations are associated with PAH metabolites in urine and DNA alterations in blood.Environ Res. 2019 Oct;177:108600. doi: 10.1016/j.envres.2019.108600. Epub 2019 Jul 22.
• [8] Regulation of CD40 signaling in colon cancer cells and its implications in clinical tissues.Cancer Immunol Immunother. 2016 Aug;65(8):919-29. doi: 10.1007/s00262-016-1847-0. Epub 2016 Jun 4.
• [9] Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes.Genes Chromosomes Cancer. 2012 May;51(5):510-20. doi: 10.1002/gcc.21939. Epub 2012 Feb 15.
• [10] Structure and polymorphisms of human aryl hydrocarbon receptor repressor (AhRR) gene in a French population: relationship with CYP1A1 inducibility and lung cancer.Pharmacogenetics. 2003 Jun;13(6):339-47. doi: 10.1097/01.fpc.0000054093.48725.79.
• [11] Association of the human aryl hydrocarbon receptor repressor (AhRR)-c.565C>G transversion with male infertility: A case-control study from Iran.J Cell Biochem. 2019 Jun;120(6):8999-9005. doi: 10.1002/jcb.28171. Epub 2018 Dec 2.
• [12] Smoking induces DNA methylation changes in Multiple Sclerosis patients with exposure-response relationship.Sci Rep. 2017 Nov 6;7(1):14589. doi: 10.1038/s41598-017-14788-w.
• [13] A Protective Role of Aryl Hydrocarbon Receptor Repressor in Inflammation and Tumor Growth.Cancers (Basel). 2019 Apr 27;11(5):589. doi: 10.3390/cancers11050589.
• [14] Offspring DNA methylation of the aryl-hydrocarbon receptor repressor gene is associated with maternal BMI, gestational age, and birth weight.Epigenetics. 2015;10(10):913-21. doi: 10.1080/15592294.2015.1078963. Epub 2015 Aug 7.
• [15] Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease.Kidney Int. 2018 Apr;93(4):986-999. doi: 10.1016/j.kint.2017.11.010. Epub 2018 Feb 1.
• [16] Association between patient age at the time of surgical treatment for endometriosis and aryl hydrocarbon receptor repressor polymorphism.Fertil Steril. 2009 Oct;92(4):1240-1242. doi: 10.1016/j.fertnstert.2009.04.041. Epub 2009 Jun 6.
• [17] Involvement of Aryl Hydrocarbon Receptor and Aryl Hydrocarbon Receptor Repressor in Helicobacter Pylori-related Gastric Pathogenesis.J Cancer. 2018 Jul 1;9(15):2757-2764. doi: 10.7150/jca.26083. eCollection 2018.
• [18] Influence of AHRR Pro189Ala polymorphism on kidney functions.Biosci Biotechnol Biochem. 2017 Jun;81(6):1120-1124. doi: 10.1080/09168451.2017.1292838. Epub 2017 Feb 20.
• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] 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.
• [22] Single and concerted effects of benzo[a]pyrene and flavonoids on the AhR and Nrf2-pathway in the human colon carcinoma cell line Caco-2. Toxicol In Vitro. 2011 Apr;25(3):671-83.
• [23] Genotoxic and epigenotoxic effects of fine particulate matter from rural and urban sites in Lebanon on human bronchial epithelial cells. Environ Res. 2015 Jan;136:352-62. doi: 10.1016/j.envres.2014.10.010. Epub 2014 Nov 25.
• [24] 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.
• [25] Suppression of WIF-1 through promoter hypermethylation causes accelerated proliferation of the aryl hydrocarbon receptor (AHR) overexpressing MCF10AT1 breast cancer cells. Toxicology. 2011 Jul 29;285(3):97-103.
• [26] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [27] 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect. 2012 Oct;120(10):1425-31. doi: 10.1289/ehp.1205412. Epub 2012 Jul 31.
• [28] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [29] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [30] Impact of eugenol and isoeugenol on AhR translocation, target gene expression, and proliferation in human HaCaT keratinocytes. J Toxicol Environ Health A. 2012;75(8-10):478-91.
• [31] Effects of human blood levels of two PAH mixtures on the AHR signalling activation pathway and CYP1A1 and COMT target genes in granulosa non-tumor and granulosa tumor cell lines. Toxicology. 2017 Aug 15;389:1-12. doi: 10.1016/j.tox.2017.07.003. Epub 2017 Jul 11.
• [32] Long interspersed element-1 is differentially regulated by food-borne carcinogens via the aryl hydrocarbon receptor. Oncogene. 2013 Oct 10;32(41):4903-12. doi: 10.1038/onc.2012.516. Epub 2012 Dec 3.