Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPU5J0S)

• DOT Name: Cytochrome P450 4A11 (CYP4A11)
• Synonyms: EC 1.14.14.1; 20-hydroxyeicosatetraenoic acid synthase; 20-HETE synthase; CYP4AII; CYPIVA11; Cytochrome P-450HK-omega; Cytochrome P450HL-omega; Fatty acid omega-hydroxylase; Lauric acid omega-hydroxylase; Long-chain fatty acid omega-monooxygenase; EC 1.14.14.80
• Gene Name: CYP4A11
• UniProt ID: CP4AB_HUMAN
• EC Number: 1.14.14.1; 1.14.14.80
• Pfam ID: PF00067
• Sequence:
  MSVSVLSPSRLLGDVSGILQAASLLILLLLLIKAVQLYLHRQWLLKALQQFPCPPSHWLF
  GHIQELQQDQELQRIQKWVETFPSACPHWLWGGKVRVQLYDPDYMKVILGRSDPKSHGSY
  RFLAPWIGYGLLLLNGQTWFQHRRMLTPAFHYDILKPYVGLMADSVRVMLDKWEELLGQD
  SPLEVFQHVSLMTLDTIMKCAFSHQGSIQVDRNSQSYIQAISDLNNLVFSRVRNAFHQND
  TIYSLTSAGRWTHRACQLAHQHTDQVIQLRKAQLQKEGELEKIKRKRHLDFLDILLLAKM
  ENGSILSDKDLRAEVDTFMFEGHDTTASGISWILYALATHPKHQERCREEIHSLLGDGAS
  ITWNHLDQMPYTTMCIKEALRLYPPVPGIGRELSTPVTFPDGRSLPKGIMVLLSIYGLHH
  NPKVWPNPEVFDPFRFAPGSAQHSHAFLPFSGGSRNCIGKQFAMNELKVATALTLLRFEL
  LPDPTRIPIPIARLVLKSKNGIHLRLRRLPNPCEDKDQL
• Function: A cytochrome P450 monooxygenase involved in the metabolism of fatty acids and their oxygenated derivatives (oxylipins). 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). Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of saturated and unsaturated fatty acids, the catalytic efficiency decreasing in the following order: dodecanoic > tetradecanoic > (9Z)-octadecenoic > (9Z,12Z)-octadecadienoic > hexadecanoic acid. Acts as a major omega-hydroxylase for dodecanoic (lauric) acid in liver. Participates in omega-hydroxylation of (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) to 20-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure. Can also catalyze the oxidation of the penultimate carbon (omega-1 oxidation) of fatty acids with lower efficiency. May contribute to the degradation of saturated very long-chain fatty acids (VLCFAs) such as docosanoic acid, by catalyzing successive omega-oxidations to the corresponding dicarboxylic acid, thereby initiating chain shortening. Omega-hydroxylates (9R,10S)-epoxy-octadecanoate stereoisomer. Plays a minor role in omega-oxidation of long-chain 3-hydroxy fatty acids. Has little activity toward prostaglandins A1 and E1.
• Tissue Specificity: Expressed in liver . Expressed in S2 and S3 segments of proximal tubules in cortex and outer medulla of kidney .
• Reactome Pathway:
  Fatty acids (R-HSA-211935)
  Miscellaneous substrates (R-HSA-211958)
  Eicosanoids (R-HSA-211979)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) (R-HSA-2142816)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Cytochrome P450 4A11 (CYP4A11) increases the abundance of Hydrogen peroxide.	[18]
Dinoprostone	DMTYOPD	Approved	Cytochrome P450 4A11 (CYP4A11) increases the secretion of Dinoprostone.	[19]
1,4-Naphthoquinone	DMTCMH7	Investigative	Cytochrome P450 4A11 (CYP4A11) increases the abundance of 1,4-Naphthoquinone.	[21]
Lauric Acid	DM9C8KQ	Investigative	Cytochrome P450 4A11 (CYP4A11) increases the metabolism of Lauric Acid.	[12]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arachidonic acid	DMUOQZD	Investigative	Cytochrome P450 4A11 (CYP4A11) increases the hydroxylation of Arachidonic acid.	[20]
20-HETE	DM5BAJ9	Investigative	Cytochrome P450 4A11 (CYP4A11) increases the chemical synthesis of 20-HETE.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cytochrome P450 4A11 (CYP4A11).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytochrome P450 4A11 (CYP4A11).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytochrome P450 4A11 (CYP4A11).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cytochrome P450 4A11 (CYP4A11).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cytochrome P450 4A11 (CYP4A11).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Cytochrome P450 4A11 (CYP4A11).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome P450 4A11 (CYP4A11).	[2]
Aspirin	DM672AH	Approved	Aspirin affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Indomethacin	DMSC4A7	Approved	Indomethacin affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Cytochrome P450 4A11 (CYP4A11).	[8]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Cytochrome P450 4A11 (CYP4A11).	[9]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Cytochrome P450 4A11 (CYP4A11).	[10]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Cytochrome P450 4A11 (CYP4A11).	[11]
Sulindac	DM2QHZU	Approved	Sulindac affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the expression of Cytochrome P450 4A11 (CYP4A11).	[12]
Clofibrate	DMPC1J7	Approved	Clofibrate increases the expression of Cytochrome P450 4A11 (CYP4A11).	[13]
Flurbiprofen	DMGN4BY	Approved	Flurbiprofen decreases the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Mefenamic acid	DMK7HFI	Approved	Mefenamic acid affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Allopurinol	DMLPAOB	Approved	Allopurinol increases the expression of Cytochrome P450 4A11 (CYP4A11).	[14]
Naproxen	DMZ5RGV	Approved	Naproxen affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Etodolac	DM6WJO9	Approved	Etodolac affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Ketoprofen	DMRKXPT	Approved	Ketoprofen affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Salicyclic acid	DM2F8XZ	Approved	Salicyclic acid affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
Oxaprozin	DM9UB0P	Approved	Oxaprozin affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
EXISULIND	DMBY56U	Phase 3	EXISULIND affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
CS-600G	DM1PV4Y	Phase 3	CS-600G affects the activity of Cytochrome P450 4A11 (CYP4A11).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cytochrome P450 4A11 (CYP4A11).	[16]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of Cytochrome P450 4A11 (CYP4A11).	[14]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Cytochrome P450 4A11 (CYP4A11).	[2]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Cytochrome P450 4A11 (CYP4A11).	[17]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) decreases the expression of Cytochrome P450 4A11 (CYP4A11).	[12]
M-Phenoxybenzoic Acid For Cis-Isomer	DMJRK47	Investigative	M-Phenoxybenzoic Acid For Cis-Isomer increases the expression of Cytochrome P450 4A11 (CYP4A11).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytochrome P450 4A11 (CYP4A11).	[15]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [2] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [3] Cisplatin-mediated cytotoxicity through inducing CYP4A 11 expression in human renal tubular epithelial cells. J Toxicol Sci. 2015 Dec;40(6):895-900.
• [4] Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells. Onco Targets Ther. 2018 May 18;11:2945-2954.
• [5] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [6] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [7] Effects of acidic non-steroidal anti-inflammatory drugs on human cytochrome P450 4A11 activity: Roles of carboxylic acid and a sulfur atom in potent inhibition by sulindac sulfide. Chem Biol Interact. 2023 Sep 1;382:110644. doi: 10.1016/j.cbi.2023.110644. Epub 2023 Jul 25.
• [8] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [9] An Evaluation of the Human Relevance of the Liver Tumors Observed in Female Mice Treated With Permethrin Based on Mode of Action. Toxicol Sci. 2020 May 1;175(1):50-63. doi: 10.1093/toxsci/kfaa017.
• [10] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [11] 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.
• [12] CYP4A11 is repressed by retinoic acid in human liver cells. FEBS Lett. 2006 Jun 12;580(14):3361-7.
• [13] Regulation of CYP4A expression by bezafibrate in primary culture of rat and human hepatocytes: interspecies difference and influence of N-acetylcysteine. Toxicol In Vitro. 2009 Oct;23(7):1259-67.
• [14] Allopurinol Protects Against Cholestatic Liver Injury in Mice Not Through Depletion of Uric Acid. Toxicol Sci. 2021 May 27;181(2):295-305. doi: 10.1093/toxsci/kfab034.
• [15] 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.
• [16] BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014 Feb 15;20(4):912-25.
• [17] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.
• [18] Human recombinant cytochrome P450 enzymes display distinct hydrogen peroxide generating activities during substrate independent NADPH oxidase reactions. Toxicol Sci. 2014 Oct;141(2):344-52. doi: 10.1093/toxsci/kfu133. Epub 2014 Jul 24.
• [19] Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):37-48.
• [20] Discovery of rubiarbonone C as a selective inhibitor of cytochrome P450 4F enzymes. Arch Toxicol. 2018 Nov;92(11):3325-3336. doi: 10.1007/s00204-018-2315-8. Epub 2018 Sep 27.
• [21] In vitro metabolism of naphthalene by human liver microsomal cytochrome P450 enzymes. Drug Metab Dispos. 2006 Jan;34(1):176-83. doi: 10.1124/dmd.105.005785. Epub 2005 Oct 21.