Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIKFYP6)

• DOT Name: Cytochrome P450 7B1 (CYP7B1)
• Synonyms: 24-hydroxycholesterol 7-alpha-hydroxylase; EC 1.14.14.26; 25/26-hydroxycholesterol 7-alpha-hydroxylase; EC 1.14.14.29; 3-hydroxysteroid 7-alpha hydroxylase; Oxysterol 7-alpha-hydroxylase
• Gene Name: CYP7B1
• Related Disease:
  Congenital bile acid synthesis defect 3
  Hereditary spastic paraplegia 5A
• UniProt ID: CP7B1_HUMAN
• EC Number: 1.14.14.26; 1.14.14.29
• Pfam ID: PF00067
• Sequence:
  MAGEVSAATGRFSLERLGLPGLALAAALLLLALCLLVRRTRRPGEPPLIKGWLPYLGVVL
  NLRKDPLRFMKTLQKQHGDTFTVLLGGKYITFILDPFQYQLVIKNHKQLSFRVFSNKLLE
  KAFSISQLQKNHDMNDELHLCYQFLQGKSLDILLESMMQNLKQVFEPQLLKTTSWDTAEL
  YPFCSSIIFEITFTTIYGKVIVCDNNKFISELRDDFLKFDDKFAYLVSNIPIELLGNVKS
  IREKIIKCFSSEKLAKMQGWSEVFQSRQDVLEKYYVHEDLEIGAHHLGFLWASVANTIPT
  MFWAMYYLLRHPEAMAAVRDEIDRLLQSTGQKKGSGFPIHLTREQLDSLICLESSIFEAL
  RLSSYSTTIRFVEEDLTLSSETGDYCVRKGDLVAIFPPVLHGDPEIFEAPEEFRYDRFIE
  DGKKKTTFFKRGKKLKCYLMPFGTGTSKCPGRFFALMEIKQLLVILLTYFDLEIIDDKPI
  GLNYSRLLFGIQYPDSDVLFRYKVKS
• Function: A cytochrome P450 monooxygenase involved in the metabolism of endogenous oxysterols and steroid hormones, including neurosteroids. 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 of steroids with a preference for 7-alpha position. Usually metabolizes steroids carrying a hydroxy group at position 3, functioning as a 3-hydroxy steroid 7-alpha hydroxylase. Hydroxylates oxysterols, including 25-hydroxycholesterol and (25R)-cholest-5-ene-3beta,26-diol toward 7-alpha hydroxy derivatives, which may be transported to the liver and converted to bile acids. Via its product 7-alpha,25-dihydroxycholesterol, a ligand for the chemotactic G protein-coupled receptor GPR183/EBI2, regulates B cell migration in germinal centers of lymphoid organs, thus guiding efficient maturation of plasma B cells and overall antigen-specific humoral immune response. 7-alpha hydroxylates neurosteroids, including 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone) and pregnenolone, both involved in hippocampus-associated memory and learning. Metabolizes androstanoids toward 6- or 7-alpha hydroxy derivatives.
• Tissue Specificity: Widely expressed. Expressed in brain, testis, ovary, prostate, liver, colon, kidney, small intestine, thymus and spleen.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Steroid hormone biosynthesis (hsa00140)
• Reactome Pathway:
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
  Synthesis of bile acids and bile salts via 27-hydroxycholesterol (R-HSA-193807)
  Endogenous sterols (R-HSA-211976)
  Defective CYP7B1 causes SPG5A and CBAS3 (R-HSA-5579013)
  Synthesis of bile acids and bile salts (R-HSA-192105)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital bile acid synthesis defect 3	DIS77JEI	Strong	Autosomal recessive	[1]
Hereditary spastic paraplegia 5A	DISOYLAP	Strong	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Cytochrome P450 7B1 (CYP7B1) increases the Metabolic disorder ADR of Chlorothiazide.	[14]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Prasterone	DM67VKL	Approved	Cytochrome P450 7B1 (CYP7B1) increases the hydroxylation of Prasterone.	[15]
27-hydroxycholesterol	DM2L6OZ	Investigative	Cytochrome P450 7B1 (CYP7B1) increases the hydroxylation of 27-hydroxycholesterol.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome P450 7B1 (CYP7B1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome P450 7B1 (CYP7B1).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cytochrome P450 7B1 (CYP7B1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytochrome P450 7B1 (CYP7B1).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Cytochrome P450 7B1 (CYP7B1).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cytochrome P450 7B1 (CYP7B1).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of Cytochrome P450 7B1 (CYP7B1).	[4]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Cytochrome P450 7B1 (CYP7B1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cytochrome P450 7B1 (CYP7B1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cytochrome P450 7B1 (CYP7B1).	[11]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Cytochrome P450 7B1 (CYP7B1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytochrome P450 7B1 (CYP7B1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Cytochrome P450 7B1 (CYP7B1).	[13]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Regulation of steroid hydroxylase CYP7B1 by androgens and estrogens in prostate cancer LNCaP cells. Biochem Biophys Res Commun. 2006 Jun 2;344(2):540-6. doi: 10.1016/j.bbrc.2006.03.175. Epub 2006 Apr 4.
• [5] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [10] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] 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.
• [14] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.
• [15] Structure and functions of human oxysterol 7alpha-hydroxylase cDNAs and gene CYP7B1. J Lipid Res. 1999 Dec;40(12):2195-203.