Details of Drug Off-Target (DOT)

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

• DOT Name: Cytochrome P450 4X1 (CYP4X1)
• Synonyms: EC 1.14.14.-; CYPIVX1
• Gene Name: CYP4X1
• Related Disease: Glioma
• UniProt ID: CP4X1_HUMAN
• EC Number: 1.14.14.-
• Pfam ID: PF00067
• Sequence:
  MEFSWLETRWARPFYLAFVFCLALGLLQAIKLYLRRQRLLRDLRPFPAPPTHWFLGHQKF
  IQDDNMEKLEEIIEKYPRAFPFWIGPFQAFFCIYDPDYAKTLLSRTDPKSQYLQKFSPPL
  LGKGLAALDGPKWFQHRRLLTPGFHFNILKAYIEVMAHSVKMMLDKWEKICSTQDTSVEV
  YEHINSMSLDIIMKCAFSKETNCQTNSTHDPYAKAIFELSKIIFHRLYSLLYHSDIIFKL
  SPQGYRFQKLSRVLNQYTDTIIQERKKSLQAGVKQDNTPKRKYQDFLDIVLSAKDESGSS
  FSDIDVHSEVSTFLLAGHDTLAASISWILYCLALNPEHQERCREEVRGILGDGSSITWDQ
  LGEMSYTTMCIKETCRLIPAVPSISRDLSKPLTFPDGCTLPAGITVVLSIWGLHHNPAVW
  KNPKVFDPLRFSQENSDQRHPYAYLPFSAGSRNCIGQEFAMIELKVTIALILLHFRVTPD
  PTRPLTFPNHFILKPKNGMYLHLKKLSEC
• Function: A cytochrome P450 monooxygenase that selectively catalyzes the epoxidation of the last double bond of the arachidonoyl moiety of anandamide, potentially modulating endocannabinoid signaling. Has no hydroxylase activity toward various fatty acids, steroids and prostaglandins. Mechanistically, 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 (CPR; NADPH-ferrihemoprotein reductase).
• Tissue Specificity: Expressed in brain, heart, kidney and skin and, at lower levels, in skeletal muscle and liver . In the brain, high levels are detected in amygdala and lower levels in globus pallidus and cerebellum . In the heart, very high levels in aorta, but very low levels in other heart regions . Also expressed in breast, prostate and colon .
• KEGG Pathway: Serotonergic sy.pse (hsa04726)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Strong	Biomarker	[1]

2 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 Cytochrome P450 4X1 (CYP4X1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytochrome P450 4X1 (CYP4X1).	[13]

14 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 Cytochrome P450 4X1 (CYP4X1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome P450 4X1 (CYP4X1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cytochrome P450 4X1 (CYP4X1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome P450 4X1 (CYP4X1).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cytochrome P450 4X1 (CYP4X1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cytochrome P450 4X1 (CYP4X1).	[7]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Cytochrome P450 4X1 (CYP4X1).	[8]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Cytochrome P450 4X1 (CYP4X1).	[9]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Cytochrome P450 4X1 (CYP4X1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cytochrome P450 4X1 (CYP4X1).	[11]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Cytochrome P450 4X1 (CYP4X1).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Cytochrome P450 4X1 (CYP4X1).	[14]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of Cytochrome P450 4X1 (CYP4X1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytochrome P450 4X1 (CYP4X1).	[16]

References

• [1] CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis.J Pharmacol Exp Ther. 2018 Apr;365(1):72-83. doi: 10.1124/jpet.117.247130. Epub 2018 Feb 1.
• [2] 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.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol. 2016 Oct;163:77-87.
• [7] 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.
• [8] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [9] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [10] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [11] 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.
• [12] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [13] 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.
• [14] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [15] Conditional regulation of the human CYP4X1 and CYP4Z1 genes. Arch Biochem Biophys. 2005 Apr 15;436(2):377-85. doi: 10.1016/j.abb.2005.02.022.
• [16] 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.