Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJBTEH8)

• DOT Name: Cytochrome P450 2J2 (CYP2J2)
• Synonyms: EC 1.14.14.-; Albendazole monooxygenase (hydroxylating); EC 1.14.14.74; Albendazole monooxygenase (sulfoxide-forming); EC 1.14.14.73; Arachidonic acid epoxygenase; CYPIIJ2; Hydroperoxy icosatetraenoate isomerase; EC 5.4.4.7
• Gene Name: CYP2J2
• UniProt ID: CP2J2_HUMAN
• EC Number: 1.14.14.-; 1.14.14.73; 1.14.14.74; 5.4.4.7
• Pfam ID: PF00067
• Sequence:
  MLAAMGSLAAALWAVVHPRTLLLGTVAFLLAADFLKRRRPKNYPPGPWRLPFLGNFFLVD
  FEQSHLEVQLFVKKYGNLFSLELGDISAVLITGLPLIKEALIHMDQNFGNRPVTPMREHI
  FKKNGLIMSSGQAWKEQRRFTLTALRNFGLGKKSLEERIQEEAQHLTEAIKEENGQPFDP
  HFKINNAVSNIICSITFGERFEYQDSWFQQLLKLLDEVTYLEASKTCQLYNVFPWIMKFL
  PGPHQTLFSNWKKLKLFVSHMIDKHRKDWNPAETRDFIDAYLKEMSKHTGNPTSSFHEEN
  LICSTLDLFFAGTETTSTTLRWALLYMALYPEIQEKVQAEIDRVIGQGQQPSTAARESMP
  YTNAVIHEVQRMGNIIPLNVPREVTVDTTLAGYHLPKGTMILTNLTALHRDPTEWATPDT
  FNPDHFLENGQFKKREAFMPFSIGKRACLGEQLARTELFIFFTSLMQKFTFRPPNNEKLS
  LKFRMGITISPVSHRLCAVPQV
• Function: A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) in the cardiovascular system. 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 (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of PUFA. Converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EpETrE), likely playing a major role in the epoxidation of endogenous cardiac arachidonic acid pools. In endothelial cells, participates in eicosanoids metabolism by converting hydroperoxide species into hydroxy epoxy metabolites. In combination with 15-lipoxygenase metabolizes arachidonic acid and converts hydroperoxyicosatetraenoates (HpETEs) into hydroxy epoxy eicosatrienoates (HEETs), which are precursors of vasodilatory trihydroxyicosatrienoic acids (THETAs). This hydroperoxide isomerase activity is NADPH- and O2-independent. Catalyzes the monooxygenation of a various xenobiotics, such as danazol, amiodarone, terfenadine, astemizole, thioridazine, tamoxifen, cyclosporin A and nabumetone. Catalyzes hydroxylation of the anthelmintics albendazole and fenbendazole. Catalyzes the sulfoxidation of fenbedazole.
• Tissue Specificity: Highly expressed in heart, present at lower levels in liver, kidney and skeletal muscle (at protein level).
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Linoleic acid metabolism (hsa00591)
  Metabolic pathways (hsa01100)
  Serotonergic sy.pse (hsa04726)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Ovarian steroidogenesis (hsa04913)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Xenobiotics (R-HSA-211981)
  Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) (R-HSA-2142670)
  Fatty acids (R-HSA-211935)
• BioCyc Pathway: MetaCyc:HS05902-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Cytochrome P450 2J2 (CYP2J2) decreases the response to substance of Arsenic trioxide.	[20]

This DOT Affected the Regulation of Drug Effects of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Cytochrome P450 2J2 (CYP2J2) increases the metabolism of Marinol.	[21]
Cannabidiol	DM0659E	Approved	Cytochrome P450 2J2 (CYP2J2) increases the metabolism of Cannabidiol.	[21]
Clozapine	DMFC71L	Approved	Cytochrome P450 2J2 (CYP2J2) increases the metabolism of Clozapine.	[22]
Anandamide	DMCKH3P	Investigative	Cytochrome P450 2J2 (CYP2J2) increases the metabolism of Anandamide.	[21]
cannabinol	DMM6A7P	Investigative	Cytochrome P450 2J2 (CYP2J2) increases the metabolism of cannabinol.	[21]
DELTA 8-TETRAHYDROCANNOBINOL	DM5ARHI	Investigative	Cytochrome P450 2J2 (CYP2J2) increases the metabolism of DELTA 8-TETRAHYDROCANNOBINOL.	[21]

This DOT Affected the Biotransformations of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Pomalidomide	DMTGBAX	Approved	Cytochrome P450 2J2 (CYP2J2) increases the oxidation of Pomalidomide.	[23]
Ebastine	DMH21D9	Phase 4	Cytochrome P450 2J2 (CYP2J2) increases the hydroxylation of Ebastine.	[24]
N-DESMETHYLCLOZAPINE	DMVIRN3	Phase 2	Cytochrome P450 2J2 (CYP2J2) increases the chemical synthesis of N-DESMETHYLCLOZAPINE.	[22]
Terfenadine	DM4KLPT	Withdrawn from market	Cytochrome P450 2J2 (CYP2J2) increases the hydroxylation of Terfenadine.	[10]
Astemizole	DM2HN6Q	Withdrawn from market	Cytochrome P450 2J2 (CYP2J2) decreases the methylation of Astemizole.	[24]

35 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 2J2 (CYP2J2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome P450 2J2 (CYP2J2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytochrome P450 2J2 (CYP2J2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome P450 2J2 (CYP2J2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome P450 2J2 (CYP2J2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome P450 2J2 (CYP2J2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cytochrome P450 2J2 (CYP2J2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cytochrome P450 2J2 (CYP2J2).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Cytochrome P450 2J2 (CYP2J2).	[10]
Fenofibrate	DMFKXDY	Approved	Fenofibrate affects the expression of Cytochrome P450 2J2 (CYP2J2).	[11]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Cytochrome P450 2J2 (CYP2J2).	[12]
Bezafibrate	DMZDCS0	Approved	Bezafibrate affects the expression of Cytochrome P450 2J2 (CYP2J2).	[11]
Nifedipine	DMSVOZT	Approved	Nifedipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Amlodipine	DMBDAZV	Approved	Amlodipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Gemfibrozil	DMD8Q3J	Approved	Gemfibrozil affects the expression of Cytochrome P450 2J2 (CYP2J2).	[11]
Felodipine	DMOSW35	Approved	Felodipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Danazol	DML8KTN	Approved	Danazol decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[14]
Nitrendipine	DM21C09	Approved	Nitrendipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Nisoldipine	DM7ISKJ	Approved	Nisoldipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Tranylcypromine	DMGB5RE	Approved	Tranylcypromine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cytochrome P450 2J2 (CYP2J2).	[15]
Benidipine	DMWNP6B	Phase 4	Benidipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Barnidipine	DMJSDBE	Phase 4	Barnidipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Azelnidipine	DMA12HL	Phase 4	Azelnidipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Telmisartan	DMS3GX2	Phase 3 Trial	Telmisartan decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Manidipine	DMJPGUA	Phase 3	Manidipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Cilnidipine	DM1975O	Phase 3	Cilnidipine decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Arc029	DMYNJHI	Phase 3	Arc029 decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Cytochrome P450 2J2 (CYP2J2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome P450 2J2 (CYP2J2).	[17]
BUTYLATEDHYDROXYTOLUENE	DMJ56MS	Phase 1	BUTYLATEDHYDROXYTOLUENE increases the expression of Cytochrome P450 2J2 (CYP2J2).	[10]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID affects the expression of Cytochrome P450 2J2 (CYP2J2).	[11]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cytochrome P450 2J2 (CYP2J2).	[19]
Alpha-naphthoflavone	DMELOIQ	Investigative	Alpha-naphthoflavone decreases the activity of Cytochrome P450 2J2 (CYP2J2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cytochrome P450 2J2 (CYP2J2).	[18]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] 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.
• [3] Differentiation-specific factors modulate epidermal CYP1-4 gene expression in human skin in response to retinoic acid and classic aryl hydrocarbon receptor ligands. J Pharmacol Exp Ther. 2006 Dec;319(3):1162-71.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] In vitro inhibition of human small intestinal and liver microsomal astemizole O-demethylation: different contribution of CYP2J2 in the small intestine and liver. Xenobiotica. 2003 Jun;33(6):615-23.
• [10] Activity, inhibition, and induction of cytochrome P450 2J2 in adult human primary cardiomyocytes. Drug Metab Dispos. 2013 Dec;41(12):2087-94.
• [11] Expression of cytochrome P450 epoxygenases and soluble epoxide hydrolase is regulated by hypolipidemic drugs in dose-dependent manner. Toxicol Appl Pharmacol. 2018 Sep 15;355:156-163.
• [12] Cytochrome P450 expression, induction and activity in human induced pluripotent stem cell-derived intestinal organoids and comparison with primary human intestinal epithelial cells and Caco-2 cells. Arch Toxicol. 2021 Mar;95(3):907-922. doi: 10.1007/s00204-020-02953-6. Epub 2020 Dec 2.
• [13] Inhibitory effects of antihypertensive drugs on human cytochrome P450 2J2 activity: Potent inhibition by azelnidipine and manidipine. Chem Biol Interact. 2019 Jun 1;306:1-9.
• [14] Inhibitory effects of Danshen components on CYP2C8 and CYP2J2. Chem Biol Interact. 2018 Jun 1;289:15-22.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [17] 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.
• [18] 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.
• [19] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [20] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [21] Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2. J Inorg Biochem. 2018 Jul;184:88-99. doi: 10.1016/j.jinorgbio.2018.03.016. Epub 2018 Apr 7.
• [22] Interindividual variation in relative CYP1A2/3A4 phenotype influences susceptibility of clozapine oxidation to cytochrome P450-specific inhibition in human hepatic microsomes. Drug Metab Dispos. 2008 Dec;36(12):2547-55. doi: 10.1124/dmd.108.023671. Epub 2008 Sep 22.
• [23] Human cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analogue of thalidomide. Chem Res Toxicol. 2014 Jan 21;27(1):147-56. doi: 10.1021/tx4004215. Epub 2013 Dec 24.
• [24] Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole. Drug Metab Dispos. 2002 Nov;30(11):1240-5.