Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT437NB2)

• DOT Name: Cytochrome P450 4F8 (CYP4F8)
• Synonyms: EC 1.14.14.1; CYPIVF8
• Gene Name: CYP4F8
• Related Disease:
  Prostate cancer
  Prostate carcinoma
• UniProt ID: CP4F8_HUMAN
• EC Number: 1.14.14.1
• Pfam ID: PF00067
• Sequence:
  MSLLSLSWLGLRPVAASPWLLLLVVGASWLLARILAWTYAFYHNGRRLRCFPQPRKQNWF
  LGHLGLVTPTEEGLRVLTQLVATYPQGFVRWLGPITPIINLCHPDIVRSVINTSDAITDK
  DIVFYKTLKPWLGDGLLLSVGDKWRHHRRLLTPAFHFNILKPYIKIFSKSANIMHAKWQR
  LAMEGSTCLDVFEHISLMTLDSLQKCIFSFDSNCQEKPSEYITAIMELSALVVKRNNQFF
  RYKDFLYFLTPCGRRFHRACRLVHDFTDAVIQERRRTLTSQGVDDFLQAKAKSKTLDFID
  VLLLSEDKNGKELSDEDIRAEADTFMFGGHDTTASGLSWVLYNLARHPEYQERCRQEVQE
  LLKDREPKEIEWDDLAQLPFLTMCLKESLRLHPPIPTFARGCTQDVVLPDSRVIPKGNVC
  NINIFAIHHNPSVWPDPEVYDPFRFDPENAQKRSPMAFIPFSAGPRNCIGQKFAMAEMKV
  VLALTLLRFRILPDHREPRRTPEIVLRAEDGLWLRVEPLG
• Function: A cytochrome P450 monooxygenase involved in the metabolism of endogenous polyunsaturated fatty acids (PUFAs) 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 the hydroxylation of carbon hydrogen bonds, with preference for omega-1 and omega-2 positions. Hydroxylates (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) predominantly at omega-2 position to form (18R)-hydroxyeicosatetraenoic acid (18R-HETE). Exhibits omega-1 hydroxylase activity toward prostaglandin (PG) H1, PGH2 and PGI2. Catalyzes the epoxidation of double bonds of PUFAs, including docosahexaenoic and docosapentaenoic acids. Shows little activity against PGD2, PGE1, PGE2, PGF2alpha, and leukotriene B4.
• Tissue Specificity: Expressed in the epithelium of seminal vesicles, in renal cortex, in adult and fetal liver, in epidermis, in corneal epithelium, in sweat glands, hair follicles, epithelial linings of the ampulla of vas deferens and of the stomach and small intestine, as well as in the transitional epithelium of the bladder and ureter (at protein level). In the epidermis, expressed from the basal cell to the granular cell layers. In the corneal epithelium, expressed in all cell layers. Also detected in prostate. Up-regulated in the epidermis of psoriatic lesions.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Eicosanoids (R-HSA-211979)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Fatty acids (R-HSA-211935)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	moderate	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome P450 4F8 (CYP4F8).	[2]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cytochrome P450 4F8 (CYP4F8).	[3]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome P450 4F8 (CYP4F8).	[4]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Cytochrome P450 4F8 (CYP4F8).	[5]

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 affects the methylation of Cytochrome P450 4F8 (CYP4F8).	[6]

References

• [1] Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer.Am J Pathol. 2011 Feb;178(2):525-36. doi: 10.1016/j.ajpath.2010.10.002.
• [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] Lavender Products Associated With Premature Thelarche and Prepubertal Gynecomastia: Case Reports and Endocrine-Disrupting Chemical Activities. J Clin Endocrinol Metab. 2019 Nov 1;104(11):5393-5405. doi: 10.1210/jc.2018-01880.
• [4] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [5] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [6] 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.