Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT92XA92)

• DOT Name: Cytochrome P450 26B1 (CYP26B1)
• Synonyms: EC 1.14.13.-; Cytochrome P450 26A2; Cytochrome P450 retinoic acid-inactivating 2; Cytochrome P450RAI-2; Retinoic acid-metabolizing cytochrome
• Gene Name: CYP26B1
• Related Disease: Lethal occipital encephalocele-skeletal dysplasia syndrome
• UniProt ID: CP26B_HUMAN
• EC Number: 1.14.13.-
• Pfam ID: PF00067
• Sequence:
  MLFEGLDLVSALATLAACLVSVTLLLAVSQQLWQLRWAATRDKSCKLPIPKGSMGFPLIG
  ETGHWLLQGSGFQSSRREKYGNVFKTHLLGRPLIRVTGAENVRKILMGEHHLVSTEWPRS
  TRMLLGPNTVSNSIGDIHRNKRKVFSKIFSHEALESYLPKIQLVIQDTLRAWSSHPEAIN
  VYQEAQKLTFRMAIRVLLGFSIPEEDLGHLFEVYQQFVDNVFSLPVDLPFSGYRRGIQAR
  QILQKGLEKAIREKLQCTQGKDYLDALDLLIESSKEHGKEMTMQELKDGTLELIFAAYAT
  TASASTSLIMQLLKHPTVLEKLRDELRAHGILHSGGCPCEGTLRLDTLSGLRYLDCVIKE
  VMRLFTPISGGYRTVLQTFELDGFQIPKGWSVMYSIRDTHDTAPVFKDVNVFDPDRFSQA
  RSEDKDGRFHYLPFGGGVRTCLGKHLAKLFLKVLAVELASTSRFELATRTFPRITLVPVL
  HPVDGLSVKFFGLDSNQNEILPETEAMLSATV
• Function: A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals. RAs exist as at least four different isomers: all-trans-RA (atRA), 9-cis-RA, 13-cis-RA, and 9,13-dicis-RA, where atRA is considered to be the biologically active isomer, although 9-cis-RA and 13-cis-RA also have activity (Probable). Catalyzes the hydroxylation of atRA primarily at C-4 and C-18, thereby contributing to the regulation of atRA homeostasis and signaling. Hydroxylation of atRA limits its biological activity and initiates a degradative process leading to its eventual elimination. Involved in the convertion of atRA to all-trans-4-oxo-RA. Can oxidize all-trans-13,14-dihydroretinoate (DRA) to metabolites which could include all-trans-4-oxo-DRA, all-trans-4-hydroxy-DRA, all-trans-5,8-epoxy-DRA, and all-trans-18-hydroxy-DRA. Shows preference for the following substrates: atRA > 9-cis-RA > 13-cis-RA. Plays a central role in germ cell development: acts by degrading RAs in the developing testis, preventing STRA8 expression, thereby leading to delay of meiosis. Required for the maintenance of the undifferentiated state of male germ cells during embryonic development in Sertoli cells, inducing arrest in G0 phase of the cell cycle and preventing meiotic entry. Plays a role in skeletal development, both at the level of patterning and in the ossification of bone and the establishment of some synovial joints. Essential for postnatal survival; Has also a significant activity in oxidation of tazarotenic acid and may therefore metabolize that xenobiotic in vivo.
• Tissue Specificity: Highly expressed in brain, particularly in the cerebellum and pons.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  RA biosynthesis pathway (R-HSA-5365859)
  Defective CYP26B1 causes RHFCA (R-HSA-5579015)
  Vitamins (R-HSA-211916)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lethal occipital encephalocele-skeletal dysplasia syndrome	DIS6NGOI	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Cytochrome P450 26B1 (CYP26B1) decreases the abundance of Tretinoin.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Cytochrome P450 26B1 (CYP26B1) decreases the response to substance of Camptothecin.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cytochrome P450 26B1 (CYP26B1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome P450 26B1 (CYP26B1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytochrome P450 26B1 (CYP26B1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytochrome P450 26B1 (CYP26B1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome P450 26B1 (CYP26B1).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytochrome P450 26B1 (CYP26B1).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Cytochrome P450 26B1 (CYP26B1).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Cytochrome P450 26B1 (CYP26B1).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Cytochrome P450 26B1 (CYP26B1).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Cytochrome P450 26B1 (CYP26B1).	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Cytochrome P450 26B1 (CYP26B1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cytochrome P450 26B1 (CYP26B1).	[14]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of Cytochrome P450 26B1 (CYP26B1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytochrome P450 26B1 (CYP26B1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytochrome P450 26B1 (CYP26B1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytochrome P450 26B1 (CYP26B1).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Cytochrome P450 26B1 (CYP26B1).	[19]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Cytochrome P450 26B1 (CYP26B1).	[20]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Cytochrome P450 26B1 (CYP26B1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytochrome P450 26B1 (CYP26B1).	[7]

References

• [1] Regulation of retinoic acid distribution is required for proximodistal patterning and outgrowth of the developing mouse limb. Dev Cell. 2004 Mar;6(3):411-22. doi: 10.1016/s1534-5807(04)00062-0.
• [2] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [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] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [7] 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.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol Toxicol. 2012 Apr;28(2):69-87.
• [11] Molecular targeting of retinoic acid metabolism in neuroblastoma: the role of the CYP26 inhibitor R116010 in vitro and in vivo. Br J Cancer. 2007 Jun 4;96(11):1675-83.
• [12] Estrogen receptor alpha (ER)-mediated coregulator binding and gene expression discriminates the toxic ER agonist diethylstilbestrol (DES) from the endogenous ER agonist 17-estradiol (E2). Cell Biol Toxicol. 2020 Oct;36(5):417-435. doi: 10.1007/s10565-020-09516-6. Epub 2020 Feb 22.
• [13] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [14] 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.
• [15] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [20] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [21] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [22] Exome-wide analyses identify low-frequency variant in CYP26B1 and additional coding variants associated with esophageal squamous cell carcinoma. Nat Genet. 2018 Mar;50(3):338-343. doi: 10.1038/s41588-018-0045-8. Epub 2018 Jan 29.
• [23] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.