Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIUY7E6)

• DOT Name: Cytochrome P450 4F12 (CYP4F12)
• Synonyms: EC 1.14.14.1; CYPIVF12
• Gene Name: CYP4F12
• UniProt ID: CP4FC_HUMAN
• EC Number: 1.14.14.1
• Pfam ID: PF00067
• Sequence:
  MSLLSLPWLGLRPVATSPWLLLLLVVGSWLLARILAWTYAFYNNCRRLQCFPQPPKRNWF
  WGHLGLITPTEEGLKNSTQMSATYSQGFTVWLGPIIPFIVLCHPDTIRSITNASAAIAPK
  DNLFIRFLKPWLGEGILLSGGDKWSRHRRMLTPAFHFNILKSYITIFNKSANIMLDKWQH
  LASEGSSRLDMFEHISLMTLDSLQKCIFSFDSHCQERPSEYIATILELSALVEKRSQHIL
  QHMDFLYYLSHDGRRFHRACRLVHDFTDAVIRERRRTLPTQGIDDFFKDKAKSKTLDFID
  VLLLSKDEDGKALSDEDIRAEADTFMFGGHDTTASGLSWVLYNLARHPEYQERCRQEVQE
  LLKDRDPKEIEWDDLAQLPFLTMCVKESLRLHPPAPFISRCCTQDIVLPDGRVIPKGITC
  LIDIIGVHHNPTVWPDPEVYDPFRFDPENSKGRSPLAFIPFSAGPRNCIGQAFAMAEMKV
  VLALMLLHFRFLPDHTEPRRKLELIMRAEGGLWLRVEPLNVSLQ
• Function: A cytochrome P450 monooxygenase involved in the metabolism of endogenous polyunsaturated fatty acids (PUFAs). 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 the hydroxylation of carbon hydrogen bonds, with preference for omega-2 position. Metabolizes (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) toward 18-hydroxy arachidonate. Catalyzes the epoxidation of double bonds of PUFAs such as docosapentaenoic and docosahexaenoic acids. Has low omega-hydroxylase activity toward leukotriene B4 and arachidonate. Involved in the metabolism of xenobiotics. Catalyzes the hydroxylation of the antihistamine drug ebastine.
• Tissue Specificity: Expressed in small intestine, liver, colon and heart.
• Reactome Pathway:
  Eicosanoids (R-HSA-211979)
  Fatty acids (R-HSA-211935)

Molecular Interaction Atlas (MIA) of This DOT

10 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 4F12 (CYP4F12).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome P450 4F12 (CYP4F12).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytochrome P450 4F12 (CYP4F12).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome P450 4F12 (CYP4F12).	[4]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Cytochrome P450 4F12 (CYP4F12).	[5]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Cytochrome P450 4F12 (CYP4F12).	[6]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Cytochrome P450 4F12 (CYP4F12).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome P450 4F12 (CYP4F12).	[1]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cytochrome P450 4F12 (CYP4F12).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cytochrome P450 4F12 (CYP4F12).	[9]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] CYP4F2 repression and a modified alpha-tocopherol (vitamin E) metabolism are two independent consequences of ethanol toxicity in human hepatocytes. Toxicol In Vitro. 2017 Apr;40:124-133.
• [6] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [7] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [8] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.