Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKHX4RF)

• DOT Name: Cytochrome P450 2S1 (CYP2S1)
• Synonyms: EC 1.14.14.-; CYPIIS1; Hydroperoxy icosatetraenoate dehydratase; EC 4.2.1.152; Thromboxane-A synthase; EC 5.3.99.5
• Gene Name: CYP2S1
• UniProt ID: CP2S1_HUMAN
• EC Number: 1.14.14.-; 4.2.1.152; 5.3.99.5
• Pfam ID: PF00067
• Sequence:
  MEATGTWALLLALALLLLLTLALSGTRARGHLPPGPTPLPLLGNLLQLRPGALYSGLMRL
  SKKYGPVFTIYLGPWRPVVVLVGQEAVREALGGQAEEFSGRGTVAMLEGTFDGHGVFFSN
  GERWRQLRKFTMLALRDLGMGKREGEELIQAEARCLVETFQGTEGRPFDPSLLLAQATSN
  VVCSLLFGLRFSYEDKEFQAVVRAAGGTLLGVSSQGGQTYEMFSWFLRPLPGPHKQLLHH
  VSTLAAFTVRQVQQHQGNLDASGPARDLVDAFLLKMAQEEQNPGTEFTNKNMLMTVIYLL
  FAGTMTVSTTVGYTLLLLMKYPHVQKWVREELNRELGAGQAPSLGDRTRLPYTDAVLHEA
  QRLLALVPMGIPRTLMRTTRFRGYTLPQGTEVFPLLGSILHDPNIFKHPEEFNPDRFLDA
  DGRFRKHEAFLPFSLGKRVCLGEGLAKAELFLFFTTILQAFSLESPCPPDTLSLKPTVSG
  LFNIPPAFQLQVRPTDLHSTTQTR
• Function: A cytochrome P450 monooxygenase involved in the metabolism of retinoids and eicosanoids. In epidermis, may contribute to the oxidative metabolism of all-trans-retinoic acid. For this activity, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Additionally, displays peroxidase and isomerase activities toward various oxygenated eicosanoids such as prostaglandin H2 (PGH2) and hydroperoxyeicosatetraenoates (HPETEs). Independently of cytochrome P450 reductase, NADPH, and O2, catalyzes the breakdown of PGH2 to hydroxyheptadecatrienoic acid (HHT) and malondialdehyde (MDA), which is known to act as a mediator of DNA damage.
• Tissue Specificity: Expressed at higher levels in extrahepatic tissues including trachea, lung, stomach, small intestine, colon, kidney, breast, placenta and spleen . Expressed in peripheral blood leukocytes . Constitutively expressed in skin (at protein level) .
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Xenobiotics (R-HSA-211981)
  CYP2E1 reactions (R-HSA-211999)
  Miscellaneous substrates (R-HSA-211958)

Molecular Interaction Atlas (MIA) of This DOT

20 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 2S1 (CYP2S1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytochrome P450 2S1 (CYP2S1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome P450 2S1 (CYP2S1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytochrome P450 2S1 (CYP2S1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cytochrome P450 2S1 (CYP2S1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cytochrome P450 2S1 (CYP2S1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cytochrome P450 2S1 (CYP2S1).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Cytochrome P450 2S1 (CYP2S1).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[11]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[9]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[9]
Flunisolide	DMZSWQC	Approved	Flunisolide decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[9]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cytochrome P450 2S1 (CYP2S1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cytochrome P450 2S1 (CYP2S1).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome P450 2S1 (CYP2S1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Cytochrome P450 2S1 (CYP2S1).	[14]

References

• [1] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Cutaneous expression of cytochrome P450 CYP2S1: individuality in regulation by therapeutic agents for psoriasis and other skin diseases. Lancet. 2003 Apr 19;361(9366):1336-43.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] CYP2S1 is negatively regulated by corticosteroids in human cell lines. Toxicol Lett. 2012 Feb 25;209(1):30-4.
• [10] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.