Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTI84H7)

• DTT Name: Cytochrome P450 1B1 (CYP1B1)
• Synonyms: CYPIB1
• Gene Name: CYP1B1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Paired donor oxygen oxidoreductase
• UniProt ID: CP1B1_HUMAN
• TTD ID: T92521
• EC Number: EC 1.14.14.-
• Sequence:
  MGTSLSPNDPWPLNPLSIQQTTLLLLLSVLATVHVGQRLLRQRRRQLRSAPPGPFAWPLI
  GNAAAVGQAAHLSFARLARRYGDVFQIRLGSCPIVVLNGERAIHQALVQQGSAFADRPAF
  ASFRVVSGGRSMAFGHYSEHWKVQRRAAHSMMRNFFTRQPRSRQVLEGHVLSEARELVAL
  LVRGSADGAFLDPRPLTVVAVANVMSAVCFGCRYSHDDPEFRELLSHNEEFGRTVGAGSL
  VDVMPWLQYFPNPVRTVFREFEQLNRNFSNFILDKFLRHCESLRPGAAPRDMMDAFILSA
  EKKAAGDSHGGGARLDLENVPATITDIFGASQDTLSTALQWLLLLFTRYPDVQTRVQAEL
  DQVVGRDRLPCMGDQPNLPYVLAFLYEAMRFSSFVPVTIPHATTANTSVLGYHIPKDTVV
  FVNQWSVNHDPLKWPNPENFDPARFLDKDGLINKDLTSRVMIFSVGKRRCIGEELSKMQL
  FLFISILAHQCDFRANPNEPAKMNFSYGLTIKPKSFKVNVTLRESMELLDSAVQNLQAKE
  TCQ
• Function: In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, retinoid and xenobiotics. Preferentially oxidizes 17beta-estradiol to the carcinogenic 4-hydroxy derivative, and a variety of procarcinogenic compounds to their activated forms, including polycyclic aromatic hydrocarbons. Promotes angiogenesis by removing cellular oxygenation products, thereby decreasing oxidative stress, release of antiangiogenic factor THBS2, then allowing endothelial cells migration, cell adhesion and capillary morphogenesis. These changes are concommitant with the endothelial nitric oxide synthase activity and nitric oxide synthesis. Plays an important role in the regulation of perivascular cell proliferation, migration, and survival through modulation of the intracellular oxidative state and NF-kappa-B expression and/or activity, during angiogenesis. Contributes to oxidative homeostasis and ultrastructural organization and function of trabecular meshwork tissue through modulation of POSTN expression. Cytochromes P450 are a group of heme-thiolate monooxygenases.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Tryptophan metabolism (hsa00380)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Ovarian steroidogenesis (hsa04913)
  Chemical carcinogenesis (hsa05204)
  MicroRNAs in cancer (hsa05206)
• Reactome Pathway: Endogenous sterols (R-HSA-211976)
• BioCyc Pathway: MetaCyc:HS06443-MON

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PINOCEMBRIN	DM96VWD	N. A.	N. A.	Phase 2	[1]
NARINGENIN	DMHAZLM	N. A.	N. A.	Phase 1	[1]

18 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-[2-(3,5-Dimethoxy-phenyl)-vinyl]-thiophene	DMX1TIU	Discovery agent	N.A.	Investigative	[2]
3-[2-(3,5-Dimethoxy-phenyl)-vinyl]-furan	DMXE1LC	Discovery agent	N.A.	Investigative	[2]
4-[2-(3,5-Dimethoxy-phenyl)-vinyl]-pyridine	DM4ENGI	Discovery agent	N.A.	Investigative	[2]
ACACETIN	DMQOB0X	Discovery agent	N.A.	Investigative	[1]
APIGENIN	DMI3491	Discovery agent	N.A.	Investigative	[1]
Chrysin	DM7V2LG	Discovery agent	N.A.	Investigative	[1]
CHRYSOERIOL	DM96ECL	Discovery agent	N.A.	Investigative	[1]
DIOSMETIN	DM4KXIM	Discovery agent	N.A.	Investigative	[1]
ERIODICTYOL	DMD3BEQ	Discovery agent	N.A.	Investigative	[1]
Galangin	DM5TQ2O	Discovery agent	N.A.	Investigative	[1]
HOMOERIODICTYOL	DM1SDN8	Discovery agent	N.A.	Investigative	[1]
ISORHAMNETIN	DMQ4Z6E	Discovery agent	N.A.	Investigative	[1]
ISOSAKUTANETIN	DMJS7MV	Discovery agent	N.A.	Investigative	[1]
KAEMPFERIDE	DMUWA2G	Discovery agent	N.A.	Investigative	[1]
KAEMPFEROL	DMHEMUB	Discovery agent	N.A.	Investigative	[1]
N-(2,4-Dimethoxy-phenyl)-3,5-dimethoxy-benzamide	DME0YBF	Discovery agent	N.A.	Investigative	[2]
TAMARIXETIN	DM0EP51	Discovery agent	N.A.	Investigative	[1]
TRISMETHOXYRESVERATROL	DM6USPC	Discovery agent	N.A.	Investigative	[2]

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Cytochrome P450 1B1 (CYP1B1) DME Info
• Gene Name: CYP1B1

15 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Amodiaquine	DME4RA8	Malaria	1F40-1F45	Approved	[3]
Caffeine	DMKBJWP	Allergic rhinitis	CA08.0	Approved	[4]
Erythromycin	DM4K7GQ	Acne vulgaris	ED80	Approved	[5]
Estradiol	DMUNTE3	Acne vulgaris	ED80	Approved	[6]
Estrone	DM5T6US	Acne vulgaris	ED80	Approved	[7]
Flutamide	DMK0O7U	Prostate cancer	2C82.0	Approved	[8]
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[9]
Melatonin	DMKWFBT	Depression	6A70-6A7Z	Approved	[10]
Oxaliplatin	DMQNWRD	Adenocarcinoma	2D40	Approved	[11]
Procarbazine	DMIK367	Hodgkin lymphoma	2B30	Approved	[12]
Progesterone	DMUY35B	Amenorrhea	GA20.0	Approved	[13]
Rosuvastatin	DMMIQ7G	Arteriosclerosis	BD40	Approved	[14]
Testosterone cypionate	DMC1TEV	N. A.	N. A.	Approved	[13]
Theophylline	DMRJFN9	Bronchitis	CA20	Approved	[4]
Vitamin A	DMJ2AH4	Night blindness	9D45	Approved	[15]

1 Clinical Trial Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
5-methoxypsoralen	DME2A8X	Psoriasis vulgaris	EA90	Phase 3	[16]

1 Investigative Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
dibutyl phthalate	DMEDGKO	Discovery agent	N.A.	Investigative	[17]

References

• [1] Selective inhibition of methoxyflavonoids on human CYP1B1 activity. Bioorg Med Chem. 2010 Sep 1;18(17):6310-5.
• [2] Design, synthesis, and discovery of novel trans-stilbene analogues as potent and selective human cytochrome P450 1B1 inhibitors. J Med Chem. 2002 Jan 3;45(1):160-4.
• [3] Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther. 2002 Feb;300(2):399-407.
• [4] Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metab Dispos. 1997 May;25(5):617-22.
• [5] Cytochromes P450 in crustacea. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998 Nov;121(1-3):157-72.
• [6] Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism. 2007 Jul;56(7):887-94.
• [7] A common CYP1B1 polymorphism is associated with 2-OHE1/16-OHE1 urinary estrone ratio. Clin Chem Lab Med. 2005;43(7):702-6.
• [8] Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation? J Pharmacol Exp Ther. 2001 Feb;296(2):537-41.
• [9] NADPH- and hydroperoxide-supported 17beta-estradiol hydroxylation catalyzed by a variant form (432L, 453S) of human cytochrome P450 1B1. J Steroid Biochem Mol Biol. 2000 Sep;74(1-2):11-8.
• [10] Metabolism of melatonin by human cytochromes p450. Drug Metab Dispos. 2005 Apr;33(4):489-94.
• [11] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [12] Tumour cytochrome P450 and drug activation. Curr Pharm Des. 2002;8(15):1335-47.
• [13] Catalytic properties of polymorphic human cytochrome P450 1B1 variants. Carcinogenesis. 1999 Aug;20(8):1607-13.
• [14] Pharmacokinetics of rosuvastatin when coadministered with rifampicin in healthy males: a randomized, single-blind, placebo-controlled, crossover study. Clin Ther. 2008 Jul;30(7):1283-9.
• [15] Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1. Drug Metab Dispos. 2004 Aug;32(8):840-7.
• [16] Cytochrome P450 CYP1B1 interacts with 8-methoxypsoralen (8-MOP) and influences psoralen-ultraviolet A (PUVA) sensitivity. PLoS One. 2013 Sep 23;8(9):e75494.
• [17] Inhibition of human cytochrome p450 1b1 further clarifies its role in the activation of dibenzo[a,l]pyrene in cells in culture. J Biochem Mol Toxicol. 2007;21(3):101-9.