Details of Drug Off-Target (DOT)

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

• DOT Name: Epoxide hydrolase 1 (EPHX1)
• Synonyms: EC 3.3.2.9; Epoxide hydratase; Microsomal epoxide hydrolase; mEH
• Gene Name: EPHX1
• Related Disease:
  Obsolete familial hypercholanemia
  Hereditary nonpolyposis colon cancer
• UniProt ID: HYEP_HUMAN
• EC Number: 3.3.2.9
• Pfam ID: PF00561
• Sequence:
  MWLEILLTSVLGFAIYWFISRDKEETLPLEDGWWGPGTRSAAREDDSIRPFKVETSDEEI
  HDLHQRIDKFRFTPPLEDSCFHYGFNSNYLKKVISYWRNEFDWKKQVEILNRYPHFKTKI
  EGLDIHFIHVKPPQLPAGHTPKPLLMVHGWPGSFYEFYKIIPLLTDPKNHGLSDEHVFEV
  ICPSIPGYGFSEASSKKGFNSVATARIFYKLMLRLGFQEFYIQGGDWGSLICTNMAQLVP
  SHVKGLHLNMALVLSNFSTLTLLLGQRFGRFLGLTERDVELLYPVKEKVFYSLMRESGYM
  HIQCTKPDTVGSALNDSPVGLAAYILEKFSTWTNTEFRYLEDGGLERKFSLDDLLTNVML
  YWTTGTIISSQRFYKENLGQGWMTQKHERMKVYVPTGFSAFPFELLHTPEKWVRFKYPKL
  ISYSYMVRGGHFAAFEEPELLAQDIRKFLSVLERQ
• Function: Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water. Plays a role in the metabolism of endogenous lipids such as epoxide-containing fatty acids. Metabolizes the abundant endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid (AA) and glycerol. Binds 20(S)-hydroxycholesterol (20(S)-OHC).
• Tissue Specificity: Found in liver.
• KEGG Pathway:
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Bile secretion (hsa04976)
  Chemical carcinogenesis - D. adducts (hsa05204)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway: Phase I - Functionalization of compounds (R-HSA-211945)
• BioCyc Pathway: MetaCyc:HS07112-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete familial hypercholanemia	DISMGYNC	Supportive	Autosomal recessive	[1]
Hereditary nonpolyposis colon cancer	DISPA49R	Limited	Autosomal dominant	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Indomethacin	DMSC4A7	Approved	Epoxide hydrolase 1 (EPHX1) increases the Metabolic disorder ADR of Indomethacin.	[34]
Mitoxantrone	DMM39BF	Approved	Epoxide hydrolase 1 (EPHX1) increases the Drug toxicity ADR of Mitoxantrone.	[34]
Phenytoin	DMNOKBV	Approved	Epoxide hydrolase 1 (EPHX1) affects the response to substance of Phenytoin.	[35]
Warfarin	DMJYCVW	Approved	Epoxide hydrolase 1 (EPHX1) increases the response to substance of Warfarin.	[36]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nimesulide	DMR1NMD	Terminated	Epoxide hydrolase 1 (EPHX1) decreases the glutathionylation of Nimesulide.	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aminohippuric acid	DMUN54G	Investigative	Epoxide hydrolase 1 (EPHX1) decreases the metabolism of Aminohippuric acid.	[38]

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 Epoxide hydrolase 1 (EPHX1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Epoxide hydrolase 1 (EPHX1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Epoxide hydrolase 1 (EPHX1).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Epoxide hydrolase 1 (EPHX1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Epoxide hydrolase 1 (EPHX1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Epoxide hydrolase 1 (EPHX1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Epoxide hydrolase 1 (EPHX1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Epoxide hydrolase 1 (EPHX1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Epoxide hydrolase 1 (EPHX1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Epoxide hydrolase 1 (EPHX1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Epoxide hydrolase 1 (EPHX1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Epoxide hydrolase 1 (EPHX1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Epoxide hydrolase 1 (EPHX1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Epoxide hydrolase 1 (EPHX1).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of Epoxide hydrolase 1 (EPHX1).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Epoxide hydrolase 1 (EPHX1).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Epoxide hydrolase 1 (EPHX1).	[7]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Epoxide hydrolase 1 (EPHX1).	[17]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Epoxide hydrolase 1 (EPHX1).	[18]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Epoxide hydrolase 1 (EPHX1).	[19]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Epoxide hydrolase 1 (EPHX1).	[16]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Epoxide hydrolase 1 (EPHX1).	[20]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Epoxide hydrolase 1 (EPHX1).	[21]
Atazanavir	DMSYRBX	Approved	Atazanavir decreases the expression of Epoxide hydrolase 1 (EPHX1).	[20]
Plicamycin	DM7C8YV	Approved	Plicamycin decreases the expression of Epoxide hydrolase 1 (EPHX1).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Epoxide hydrolase 1 (EPHX1).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Epoxide hydrolase 1 (EPHX1).	[24]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the expression of Epoxide hydrolase 1 (EPHX1).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Epoxide hydrolase 1 (EPHX1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Epoxide hydrolase 1 (EPHX1).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Epoxide hydrolase 1 (EPHX1).	[25]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Epoxide hydrolase 1 (EPHX1).	[30]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Epoxide hydrolase 1 (EPHX1).	[31]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Epoxide hydrolase 1 (EPHX1).	[32]
Forskolin	DM6ITNG	Investigative	Forskolin affects the expression of Epoxide hydrolase 1 (EPHX1).	[33]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Epoxide hydrolase 1 (EPHX1).	[25]

References

• [1] Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia. Biochim Biophys Acta. 2003 Jul 30;1638(3):208-16. doi: 10.1016/s0925-4439(03)00085-1.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] 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.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 2004 Jun 15;64(12):4218-26.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [11] 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.
• [12] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [13] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [14] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] 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.
• [17] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [18] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [19] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [20] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [21] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [22] Sp1 and Sp3 transcription factors regulate the basal expression of human microsomal epoxide hydrolase (EPHX1) through interaction with the E1b far upstream promoter. Gene. 2014 Feb 15;536(1):135-44. doi: 10.1016/j.gene.2013.11.053. Epub 2013 Dec 4.
• [23] Lung carcinogenesis: resveratrol modulates the expression of genes involved in the metabolism of PAH in human bronchial epithelial cells. Int J Cancer. 2001 Apr 1;92(1):18-25.
• [24] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [25] Intronic DNA elements regulate Nrf2 chemical responsiveness of the human microsomal epoxide hydrolase gene (EPHX1) through a far upstream alternative promoter. Biochim Biophys Acta. 2014 Jun;1839(6):493-505. doi: 10.1016/j.bbagrm.2014.03.014. Epub 2014 Apr 2.
• [26] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [27] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [28] 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.
• [29] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [30] Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology. 2020 Nov;444:152582. doi: 10.1016/j.tox.2020.152582. Epub 2020 Sep 6.
• [31] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [32] Butyrate interacts with benzo[a]pyrene to alter expression and activities of xenobiotic metabolizing enzymes involved in metabolism of carcinogens within colon epithelial cell models. Toxicology. 2019 Jan 15;412:1-11.
• [33] The effect of valproate and levetiracetam on steroidogenesis in forskolin-stimulated H295R cells. Epilepsia. 2010 Nov;51(11):2280-8.
• [34] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [35] Maternal EPHX1 polymorphisms and risk of phenytoin-induced congenital malformations. Pharmacogenet Genomics. 2010 Jan;20(1):58-63. doi: 10.1097/FPC.0b013e328334b6a3.
• [36] Building individualized medicine: prevention of adverse reactions to warfarin therapy. J Pharmacol Exp Ther. 2007 Aug;322(2):427-34. doi: 10.1124/jpet.106.117952. Epub 2007 May 11.
• [37] Chemical and Enzymatic Transformations of Nimesulide to GSH Conjugates through Reductive and Oxidative Mechanisms. Chem Res Toxicol. 2015 Dec 21;28(12):2267-77. doi: 10.1021/acs.chemrestox.5b00290. Epub 2015 Nov 12.
• [38] Occupational exposure to polycyclic aromatic hydrocarbons in German industries: association between exogenous exposure and urinary metabolites and its modulation by enzyme polymorphisms. Toxicol Lett. 2005 Jul 4;157(3):241-55. doi: 10.1016/j.toxlet.2005.02.012. Epub 2005 Apr 8.