Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRI4UR1)

• DOT Name: 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1)
• Synonyms: EC 1.14.14.139; 7-alpha-hydroxy-4-cholesten-3-one 12-alpha-hydroxylase; CYPVIIIB1; Cytochrome P450 8B1; Sterol 12-alpha-hydroxylase
• Gene Name: CYP8B1
• UniProt ID: CP8B1_HUMAN
• PDB ID: 7LYX; 8EOH
• EC Number: 1.14.14.139
• Pfam ID: PF00067
• Sequence:
  MVLWGPVLGALLVVIAGYLCLPGMLRQRRPWEPPLDKGTVPWLGHAMAFRKNMFEFLKRM
  RTKHGDVFTVQLGGQYFTFVMDPLSFGSILKDTQRKLDFGQYAKKLVLKVFGYRSVQGDH
  EMIHSASTKHLRGDGLKDLNETMLDSLSFVMLTSKGWSLDASCWHEDSLFRFCYYILFTA
  GYLSLFGYTKDKEQDLLQAGELFMEFRKFDLLFPRFVYSLLWPREWLEVGRLQRLFHKML
  SVSHSQEKEGISNWLGNMLQFLREQGVPSAMQDKFNFMMLWASQGNTGPTSFWALLYLLK
  HPEAIRAVREEATQVLGEARLETKQSFAFKLGALQHTPVLDSVVEETLRLRAAPTLLRLV
  HEDYTLKMSSGQEYLFRHGDILALFPYLSVHMDPDIHPEPTVFKYDRFLNPNGSRKVDFF
  KTGKKIHHYTMPWGSGVSICPGRFFALSEVKLFILLMVTHFDLELVDPDTPLPHVDPQRW
  GFGTMQPSHDVRFRYRLHPTE
• Function: A cytochrome P450 monooxygenase involved in primary bile acid biosynthesis. Catalyzes the 12alpha-hydroxylation of 7alpha-hydroxy-4-cholesten-3-one, an intermediate metabolite in cholic acid biosynthesis. Controls biliary balance of cholic acid and chenodeoxycholic acid, ultimately regulating the intestinal absorption of dietary lipids. 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--hemoprotein reductase).
• Tissue Specificity: Liver.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Metabolic pathways (hsa01100)
  PPAR sig.ling pathway (hsa03320)
• Reactome Pathway:
  Synthesis of bile acids and bile salts via 24-hydroxycholesterol (R-HSA-193775)
  Synthesis of bile acids and bile salts via 27-hydroxycholesterol (R-HSA-193807)
  Nicotinamide salvaging (R-HSA-197264)
  Eicosanoids (R-HSA-211979)
  Sterols are 12-hydroxylated by CYP8B1 (R-HSA-211994)
  Synthesis of Prostaglandins (PG) and Thromboxanes (TX) (R-HSA-2162123)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[6]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[7]
Lindane	DMB8CNL	Approved	Lindane increases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[8]
Ritonavir	DMU764S	Approved	Ritonavir decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[9]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[10]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[10]
Clavulanate	DM2FGRT	Approved	Clavulanate decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[11]
Cholic acid	DM7OKQV	Approved	Cholic acid decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[12]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[13]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[11]
2-arachidonoylglycerol	DMM0KOJ	Investigative	2-arachidonoylglycerol increases the expression of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1).	[4]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [7] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [8] Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice. Environ Pollut. 2017 Jul;226:268-276.
• [9] Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
• [10] Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures. Toxicol Sci. 2014 Oct;141(2):538-46. doi: 10.1093/toxsci/kfu151. Epub 2014 Jul 23.
• [11] Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [15] Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. PLoS One. 2013 Jul 22;8(7):e68845.