Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFE4EYE)

• DOT Name: Aryl hydrocarbon receptor (AHR)
• Synonyms: Ah receptor; AhR; Class E basic helix-loop-helix protein 76; bHLHe76
• Gene Name: AHR
• Related Disease:
  Retinitis pigmentosa 85
  Retinitis pigmentosa
  Foveal hypoplasia
• UniProt ID: AHR_HUMAN
• PDB ID: 5NJ8; 7ZUB
• Pfam ID: PF00010 ; PF00989 ; PF08447
• Sequence:
  MNSSSANITYASRKRRKPVQKTVKPIPAEGIKSNPSKRHRDRLNTELDRLASLLPFPQDV
  INKLDKLSVLRLSVSYLRAKSFFDVALKSSPTERNGGQDNCRAANFREGLNLQEGEFLLQ
  ALNGFVLVVTTDALVFYASSTIQDYLGFQQSDVIHQSVYELIHTEDRAEFQRQLHWALNP
  SQCTESGQGIEEATGLPQTVVCYNPDQIPPENSPLMERCFICRLRCLLDNSSGFLAMNFQ
  GKLKYLHGQKKKGKDGSILPPQLALFAIATPLQPPSILEIRTKNFIFRTKHKLDFTPIGC
  DAKGRIVLGYTEAELCTRGSGYQFIHAADMLYCAESHIRMIKTGESGMIVFRLLTKNNRW
  TWVQSNARLLYKNGRPDYIIVTQRPLTDEEGTEHLRKRNTKLPFMFTTGEAVLYEATNPF
  PAIMDPLPLRTKNGTSGKDSATTSTLSKDSLNPSSLLAAMMQQDESIYLYPASSTSSTAP
  FENNFFNESMNECRNWQDNTAPMGNDTILKHEQIDQPQDVNSFAGGHPGLFQDSKNSDLY
  SIMKNLGIDFEDIRHMQNEKFFRNDFSGEVDFRDIDLTDEILTYVQDSLSKSPFIPSDYQ
  QQQSLALNSSCMVQEHLHLEQQQQHHQKQVVVEPQQQLCQKMKHMQVNGMFENWNSNQFV
  PFNCPQQDPQQYNVFTDLHGISQEFPYKSEMDSMPYTQNFISCNQPVLPQHSKCTELDYP
  MGSFEPSPYPTTSSLEDFVTCLQLPENQKHGLNPQSAIITPQTCYAGAVSMYQCQPEPQH
  THVGQMQYNPVLPGQQAFLNKFQNGVLNETYPAELNNINNTQTTTHLQPLHHPSEARPFP
  DLTSSGFL
• Function: Ligand-activated transcription factor that enables cells to adapt to changing conditions by sensing compounds from the environment, diet, microbiome and cellular metabolism, and which plays important roles in development, immunity and cancer. Upon ligand binding, translocates into the nucleus, where it heterodimerizes with ARNT and induces transcription by binding to xenobiotic response elements (XRE). Regulates a variety of biological processes, including angiogenesis, hematopoiesis, drug and lipid metabolism, cell motility and immune modulation. Xenobiotics can act as ligands: upon xenobiotic-binding, activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Next to xenobiotics, natural ligands derived from plants, microbiota, and endogenous metabolism are potent AHR agonists. Tryptophan (Trp) derivatives constitute an important class of endogenous AHR ligands. Acts as a negative regulator of anti-tumor immunity: indoles and kynurenic acid generated by Trp catabolism act as ligand and activate AHR, thereby promoting AHR-driven cancer cell motility and suppressing adaptive immunity. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-BMAL1 heterodimer mediated transcriptional activation of PER1. The heterodimer ARNT:AHR binds to core DNA sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of target gene promoters and activates their transcription.
• Tissue Specificity: Expressed in all tissues tested including blood, brain, heart, kidney, liver, lung, pancreas and skeletal muscle. Expressed in retinal photoreceptors .
• KEGG Pathway:
  Th17 cell differentiation (hsa04659)
  Cushing syndrome (hsa04934)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinitis pigmentosa 85	DISRGLEP	Strong	Autosomal recessive	[1]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[2]
Foveal hypoplasia	DISENLGC	Limited	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Aryl hydrocarbon receptor (AHR).	[4]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Aryl hydrocarbon receptor (AHR).	[62]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aryl hydrocarbon receptor (AHR).	[71]

86 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 Aryl hydrocarbon receptor (AHR).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Aryl hydrocarbon receptor (AHR).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Aryl hydrocarbon receptor (AHR).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Aryl hydrocarbon receptor (AHR).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Aryl hydrocarbon receptor (AHR).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Aryl hydrocarbon receptor (AHR).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Aryl hydrocarbon receptor (AHR).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Aryl hydrocarbon receptor (AHR).	[12]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Aryl hydrocarbon receptor (AHR).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Aryl hydrocarbon receptor (AHR).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Aryl hydrocarbon receptor (AHR).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of Aryl hydrocarbon receptor (AHR).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate affects the activity of Aryl hydrocarbon receptor (AHR).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Aryl hydrocarbon receptor (AHR).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Aryl hydrocarbon receptor (AHR).	[20]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Aryl hydrocarbon receptor (AHR).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Aryl hydrocarbon receptor (AHR).	[22]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Aryl hydrocarbon receptor (AHR).	[24]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Aryl hydrocarbon receptor (AHR).	[25]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Aryl hydrocarbon receptor (AHR).	[26]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the activity of Aryl hydrocarbon receptor (AHR).	[27]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Aryl hydrocarbon receptor (AHR).	[28]
Cidofovir	DMA13GD	Approved	Cidofovir affects the activity of Aryl hydrocarbon receptor (AHR).	[17]
Fenofibrate	DMFKXDY	Approved	Fenofibrate affects the activity of Aryl hydrocarbon receptor (AHR).	[17]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Aryl hydrocarbon receptor (AHR).	[29]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the activity of Aryl hydrocarbon receptor (AHR).	[30]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the activity of Aryl hydrocarbon receptor (AHR).	[17]
Clodronate	DM9Y6X7	Approved	Clodronate affects the activity of Aryl hydrocarbon receptor (AHR).	[17]
Lindane	DMB8CNL	Approved	Lindane affects the expression of Aryl hydrocarbon receptor (AHR).	[32]
Colchicine	DM2POTE	Approved	Colchicine decreases the activity of Aryl hydrocarbon receptor (AHR).	[33]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of Aryl hydrocarbon receptor (AHR).	[34]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil affects the activity of Aryl hydrocarbon receptor (AHR).	[17]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Aryl hydrocarbon receptor (AHR).	[35]
Isoproterenol	DMK7MEY	Approved	Isoproterenol increases the expression of Aryl hydrocarbon receptor (AHR).	[36]
Eicosapentaenoic acid/docosa-hexaenoic acid	DMMUCG4	Approved	Eicosapentaenoic acid/docosa-hexaenoic acid increases the expression of Aryl hydrocarbon receptor (AHR).	[37]
Cantharidin	DMBP5N3	Approved	Cantharidin increases the expression of Aryl hydrocarbon receptor (AHR).	[38]
Omeprazole	DM471KJ	Approved	Omeprazole decreases the expression of Aryl hydrocarbon receptor (AHR).	[39]
Cimetidine	DMH61ZB	Approved	Cimetidine affects the expression of Aryl hydrocarbon receptor (AHR).	[29]
Clotrimazole	DMMFCIH	Approved	Clotrimazole increases the activity of Aryl hydrocarbon receptor (AHR).	[30]
Busulfan	DMXYJ9C	Approved	Busulfan increases the expression of Aryl hydrocarbon receptor (AHR).	[40]
Epanova	DMHEAGL	Approved	Epanova affects the activity of Aryl hydrocarbon receptor (AHR).	[41]
Citalopram	DM2G9AE	Approved	Citalopram decreases the expression of Aryl hydrocarbon receptor (AHR).	[42]
Plicamycin	DM7C8YV	Approved	Plicamycin decreases the expression of Aryl hydrocarbon receptor (AHR).	[43]
Felodipine	DMOSW35	Approved	Felodipine increases the activity of Aryl hydrocarbon receptor (AHR).	[44]
Isradipine	DMA5XGH	Approved	Isradipine increases the activity of Aryl hydrocarbon receptor (AHR).	[44]
Doxycycline	DM7ICNU	Approved	Doxycycline increases the expression of Aryl hydrocarbon receptor (AHR).	[45]
L-tryptophan	DMIBH7M	Approved	L-tryptophan increases the expression of Aryl hydrocarbon receptor (AHR).	[46]
Tranilast	DME5Y64	Approved	Tranilast increases the expression of Aryl hydrocarbon receptor (AHR).	[39]
Herbimycin A	DM6YWBF	Approved	Herbimycin A decreases the expression of Aryl hydrocarbon receptor (AHR).	[47]
Berberine	DMC5Q8X	Phase 4	Berberine increases the activity of Aryl hydrocarbon receptor (AHR).	[48]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the activity of Aryl hydrocarbon receptor (AHR).	[49]
Benidipine	DMWNP6B	Phase 4	Benidipine increases the activity of Aryl hydrocarbon receptor (AHR).	[44]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Aryl hydrocarbon receptor (AHR).	[50]
I3C	DMIGFOR	Phase 3	I3C increases the expression of Aryl hydrocarbon receptor (AHR).	[52]
Genistein	DM0JETC	Phase 2/3	Genistein affects the activity of Aryl hydrocarbon receptor (AHR).	[53]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone affects the expression of Aryl hydrocarbon receptor (AHR).	[40]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Aryl hydrocarbon receptor (AHR).	[54]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the activity of Aryl hydrocarbon receptor (AHR).	[55]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Aryl hydrocarbon receptor (AHR).	[56]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Aryl hydrocarbon receptor (AHR).	[57]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN increases the expression of Aryl hydrocarbon receptor (AHR).	[38]
G1	DMTV42K	Phase 1/2	G1 increases the expression of Aryl hydrocarbon receptor (AHR).	[58]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Aryl hydrocarbon receptor (AHR).	[59]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Aryl hydrocarbon receptor (AHR).	[60]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Aryl hydrocarbon receptor (AHR).	[61]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the activity of Aryl hydrocarbon receptor (AHR).	[63]
Eugenol	DM7US1H	Patented	Eugenol increases the activity of Aryl hydrocarbon receptor (AHR).	[64]
PMID26560530-Compound-34	DMLGZPO	Patented	PMID26560530-Compound-34 increases the activity of Aryl hydrocarbon receptor (AHR).	[65]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin decreases the expression of Aryl hydrocarbon receptor (AHR).	[47]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the expression of Aryl hydrocarbon receptor (AHR).	[66]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of Aryl hydrocarbon receptor (AHR).	[67]
Baicalin	DMY1TLZ	Terminated	Baicalin increases the activity of Aryl hydrocarbon receptor (AHR).	[70]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Aryl hydrocarbon receptor (AHR).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Aryl hydrocarbon receptor (AHR).	[72]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Aryl hydrocarbon receptor (AHR).	[73]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Aryl hydrocarbon receptor (AHR).	[40]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the expression of Aryl hydrocarbon receptor (AHR).	[74]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Aryl hydrocarbon receptor (AHR).	[75]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Aryl hydrocarbon receptor (AHR).	[77]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of Aryl hydrocarbon receptor (AHR).	[78]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid increases the expression of Aryl hydrocarbon receptor (AHR).	[80]
Chrysin	DM7V2LG	Investigative	Chrysin affects the activity of Aryl hydrocarbon receptor (AHR).	[53]
Kaempferol	DMHEMUB	Investigative	Kaempferol increases the activity of Aryl hydrocarbon receptor (AHR).	[81]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Investigative	(E)-4-(3,5-dimethoxystyryl)phenol increases the activity of Aryl hydrocarbon receptor (AHR).	[82]
Paraoxon	DMN4ZKC	Investigative	Paraoxon increases the expression of Aryl hydrocarbon receptor (AHR).	[24]
PD98059	DMZC90M	Investigative	PD98059 increases the expression of Aryl hydrocarbon receptor (AHR).	[79]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Progesterone affects the binding of Aryl hydrocarbon receptor (AHR).	[19]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol affects the binding of Aryl hydrocarbon receptor (AHR).	[23]
Sulindac	DM2QHZU	Approved	Sulindac increases the localization of Aryl hydrocarbon receptor (AHR).	[31]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone affects the binding of Aryl hydrocarbon receptor (AHR).	[23]
Curcumin	DMQPH29	Phase 3	Curcumin increases the degradation of Aryl hydrocarbon receptor (AHR).	[51]
Acteoside	DM0YHKB	Terminated	Acteoside decreases the localization of Aryl hydrocarbon receptor (AHR).	[68]
Pifithrin-alpha	DM63OD7	Terminated	Pifithrin-alpha affects the localization of Aryl hydrocarbon receptor (AHR).	[69]
Forskolin	DM6ITNG	Investigative	Forskolin affects the localization of Aryl hydrocarbon receptor (AHR).	[76]
U0126	DM31OGF	Investigative	U0126 affects the localization of Aryl hydrocarbon receptor (AHR).	[79]
Rutin	DMEHRAJ	Investigative	Rutin decreases the localization of Aryl hydrocarbon receptor (AHR).	[68]
Daidzein	DMRFTJX	Investigative	Daidzein affects the binding of Aryl hydrocarbon receptor (AHR).	[23]

References

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