Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY687L9)

• DOT Name: Cytochrome P450 2C18 (CYP2C18)
• Synonyms: EC 1.14.14.1; CYPIIC18; Cytochrome P450-6b/29c
• Gene Name: CYP2C18
• UniProt ID: CP2CI_HUMAN
• PDB ID: 2CIK; 2H6P
• EC Number: 1.14.14.1
• Pfam ID: PF00067
• Sequence:
  MDPAVALVLCLSCLFLLSLWRQSSGRGRLPSGPTPLPIIGNILQLDVKDMSKSLTNFSKV
  YGPVFTVYFGLKPIVVLHGYEAVKEALIDHGEEFSGRGSFPVAEKVNKGLGILFSNGKRW
  KEIRRFCLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTNASPCDPTFILGCAPCNVICS
  VIFHDRFDYKDQRFLNLMEKFNENLRILSSPWIQVCNNFPALIDYLPGSHNKIAENFAYI
  KSYVLERIKEHQESLDMNSARDFIDCFLIKMEQEKHNQQSEFTVESLIATVTDMFGAGTE
  TTSTTLRYGLLLLLKYPEVTAKVQEEIECVVGRNRSPCMQDRSHMPYTDAVVHEIQRYID
  LLPTNLPHAVTCDVKFKNYLIPKGTTIITSLTSVLHNDKEFPNPEMFDPGHFLDKSGNFK
  KSDYFMPFSAGKRMCMGEGLARMELFLFLTTILQNFNLKSQVDPKDIDITPIANAFGRVP
  PLYQLCFIPV
• Function: A cytochrome P450 monooxygenase involved in retinoid metabolism. Hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may modulate atRA signaling and clearance. 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).
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
  Serotonergic sy.pse (hsa04726)
  Chemical carcinogenesis - D. adducts (hsa05204)
• Reactome Pathway: Xenobiotics (R-HSA-211981)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclophosphamide	DM4O2Z7	Approved	Cytochrome P450 2C18 (CYP2C18) increases the activity of Cyclophosphamide.	[10]
Ifosfamide	DMCT3I8	Approved	Cytochrome P450 2C18 (CYP2C18) increases the activity of Ifosfamide.	[10]
Warfarin	DMJYCVW	Approved	Cytochrome P450 2C18 (CYP2C18) affects the response to substance of Warfarin.	[11]
Acenocoumarol	DMH75KV	Approved	Cytochrome P450 2C18 (CYP2C18) affects the response to substance of Acenocoumarol.	[15]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Cytochrome P450 2C18 (CYP2C18) decreases the response to substance of Chlorpromazine.	[16]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Cytochrome P450 2C18 (CYP2C18) decreases the response to substance of Amiodarone.	[16]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Amodiaquine	DME4RA8	Approved	Cytochrome P450 2C18 (CYP2C18) increases the metabolism of Amodiaquine.	[12]
Dronedarone	DMA8FS5	Approved	Cytochrome P450 2C18 (CYP2C18) increases the metabolism of Dronedarone.	[14]
1,4-Naphthoquinone	DMTCMH7	Investigative	Cytochrome P450 2C18 (CYP2C18) increases the abundance of 1,4-Naphthoquinone.	[17]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Lansoprazole	DMXYLQ3	Approved	Cytochrome P450 2C18 (CYP2C18) increases the hydroxylation of Lansoprazole.	[13]

7 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 2C18 (CYP2C18).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytochrome P450 2C18 (CYP2C18).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome P450 2C18 (CYP2C18).	[3]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Cytochrome P450 2C18 (CYP2C18).	[4]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cytochrome P450 2C18 (CYP2C18).	[6]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Cytochrome P450 2C18 (CYP2C18).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cytochrome P450 2C18 (CYP2C18).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Cytochrome P450 2C18 (CYP2C18).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cytochrome P450 2C18 (CYP2C18).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cytochrome P450 2C18 (CYP2C18).	[5]

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] 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.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [10] Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation. Pharmacogenetics. 1997 Jun;7(3):211-21.
• [11] Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenet Genomics. 2009 Oct;19(10):800-12. doi: 10.1097/FPC.0b013e3283317ab5.
• [12] Apoptosis contributes to the cytotoxicity induced by amodiaquine and its major metabolite N-desethylamodiaquine in hepatic cells. Toxicol In Vitro. 2020 Feb;62:104669. doi: 10.1016/j.tiv.2019.104669. Epub 2019 Oct 16.
• [13] Oxidative metabolism of lansoprazole by human liver cytochromes P450. Mol Pharmacol. 1995 Feb;47(2):410-8.
• [14] The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone. Arch Toxicol. 2018 Jun;92(6):1969-1981. doi: 10.1007/s00204-018-2196-x. Epub 2018 Apr 3.
• [15] A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet. 2009 Oct 1;18(19):3758-68. doi: 10.1093/hmg/ddp309. Epub 2009 Jul 4.
• [16] Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity. Chem Biol Interact. 2016 Aug 5;255:63-73. doi: 10.1016/j.cbi.2015.10.009. Epub 2015 Oct 22.
• [17] 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.