Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8Z5KLD)

• DOT Name: Cytochrome P450 7A1 (CYP7A1)
• Synonyms: 24-hydroxycholesterol 7-alpha-hydroxylase; EC 1.14.14.26; CYPVII; Cholesterol 7-alpha-hydroxylase; Cholesterol 7-alpha-monooxygenase; EC 1.14.14.23
• Gene Name: CYP7A1
• Related Disease: Hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency
• UniProt ID: CP7A1_HUMAN
• PDB ID: 3DAX; 3SN5; 3V8D
• EC Number: 1.14.14.23; 1.14.14.26
• Pfam ID: PF00067
• Sequence:
  MMTTSLIWGIAIAACCCLWLILGIRRRQTGEPPLENGLIPYLGCALQFGANPLEFLRANQ
  RKHGHVFTCKLMGKYVHFITNPLSYHKVLCHGKYFDWKKFHFATSAKAFGHRSIDPMDGN
  TTENINDTFIKTLQGHALNSLTESMMENLQRIMRPPVSSNSKTAAWVTEGMYSFCYRVMF
  EAGYLTIFGRDLTRRDTQKAHILNNLDNFKQFDKVFPALVAGLPIHMFRTAHNAREKLAE
  SLRHENLQKRESISELISLRMFLNDTLSTFDDLEKAKTHLVVLWASQANTIPATFWSLFQ
  MIRNPEAMKAATEEVKRTLENAGQKVSLEGNPICLSQAELNDLPVLDSIIKESLRLSSAS
  LNIRTAKEDFTLHLEDGSYNIRKDDIIALYPQLMHLDPEIYPDPLTFKYDRYLDENGKTK
  TTFYCNGLKLKYYYMPFGSGATICPGRLFAIHEIKQFLILMLSYFELELIEGQAKCPPLD
  QSRAGLGILPPLNDIEFKYKFKHL
• Function: A cytochrome P450 monooxygenase involved in the metabolism of endogenous cholesterol and its oxygenated derivatives (oxysterols). 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). Functions as a critical regulatory enzyme of bile acid biosynthesis and cholesterol homeostasis. Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of cholesterol, a rate-limiting step in cholesterol catabolism and bile acid biosynthesis. 7-alpha hydroxylates several oxysterols, including 4beta-hydroxycholesterol and 24-hydroxycholesterol. Catalyzes the oxidation of the 7,8 double bond of 7-dehydrocholesterol and lathosterol with direct and predominant formation of the 7-keto derivatives.
• Tissue Specificity: Detected in liver.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  PPAR sig.ling pathway (hsa03320)
  Bile secretion (hsa04976)
  Cholesterol metabolism (hsa04979)
• 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)
  PPARA activates gene expression (R-HSA-1989781)
  Endogenous sterols (R-HSA-211976)
  Synthesis of bile acids and bile salts (R-HSA-192105)
• BioCyc Pathway: MetaCyc:HS09659-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency	DISY0P6K	Supportive	Semidominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
27-hydroxycholesterol	DM2L6OZ	Investigative	Cytochrome P450 7A1 (CYP7A1) increases the metabolism of 27-hydroxycholesterol.	[35]
25-hydroxycholesterol	DMCHAQ7	Investigative	Cytochrome P450 7A1 (CYP7A1) increases the metabolism of 25-hydroxycholesterol.	[35]
24(S)-hydroxycholesterol	DMGMWA6	Investigative	Cytochrome P450 7A1 (CYP7A1) increases the metabolism of 24(S)-hydroxycholesterol.	[36]

44 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 Cytochrome P450 7A1 (CYP7A1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytochrome P450 7A1 (CYP7A1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[7]
Triclosan	DMZUR4N	Approved	Triclosan affects the expression of Cytochrome P450 7A1 (CYP7A1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Cytochrome P450 7A1 (CYP7A1).	[10]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[12]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[13]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[14]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[15]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Cytochrome P450 7A1 (CYP7A1).	[16]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[17]
Ritonavir	DMU764S	Approved	Ritonavir decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[18]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[19]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[20]
Bosentan	DMIOGBU	Approved	Bosentan decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[21]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[14]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[17]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[22]
Atazanavir	DMSYRBX	Approved	Atazanavir decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[19]
Clavulanate	DM2FGRT	Approved	Clavulanate decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[23]
Methoxsalen	DME8FZ9	Approved	Methoxsalen decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[24]
Cholic acid	DM7OKQV	Approved	Cholic acid decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[17]
Gemfibrozil	DMD8Q3J	Approved	Gemfibrozil decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[14]
Calcipotriol	DM03CP7	Approved	Calcipotriol decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[25]
Saracatinib	DMBLHGP	Phase 2	Saracatinib increases the expression of Cytochrome P450 7A1 (CYP7A1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[26]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[8]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Cytochrome P450 7A1 (CYP7A1).	[29]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[30]
	DM9CEI5		decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[31]
NSC-1771	DMNXDGQ	Investigative	NSC-1771 decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[30]
Hyperforin	DM2L3PE	Investigative	Hyperforin decreases the expression of Cytochrome P450 7A1 (CYP7A1).	[32]
Icariside II	DM3DB8X	Investigative	Icariside II increases the expression of Cytochrome P450 7A1 (CYP7A1).	[33]
2-arachidonoylglycerol	DMM0KOJ	Investigative	2-arachidonoylglycerol increases the expression of Cytochrome P450 7A1 (CYP7A1).	[34]

References

• [1] Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest. 2002 Jul;110(1):109-17. doi: 10.1172/JCI15387.
• [2] 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.
• [3] 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.
• [4] Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells. Hepatology. 2011 Feb;53(2):548-57. doi: 10.1002/hep.24047. Epub 2010 Dec 10.
• [5] Identification of a novel farnesoid X receptor agonist, kaempferol-7-O-rhamnoside, a compound ameliorating drug-induced liver injury based on virtual screening and in vitro validation. Toxicol Appl Pharmacol. 2022 Nov 1;454:116251. doi: 10.1016/j.taap.2022.116251. Epub 2022 Sep 20.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] A novel bile acid-activated vitamin D receptor signaling in human hepatocytes. Mol Endocrinol. 2010 Jun;24(6):1151-64.
• [8] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] 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.
• [11] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [12] 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.
• [13] The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. Mol Pharmacol. 2005 Aug;68(2):551-8. doi: 10.1124/mol.105.012104. Epub 2005 May 23.
• [14] Fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients. Eur J Clin Pharmacol. 2004 Feb;59(12):855-61. doi: 10.1007/s00228-003-0704-1. Epub 2003 Dec 18.
• [15] Species-specific mechanisms for cholesterol 7alpha-hydroxylase (CYP7A1) regulation by drugs and bile acids. Arch Biochem Biophys. 2005 Feb 1;434(1):75-85.
• [16] Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice. Environ Pollut. 2017 Jul;226:268-276.
• [17] The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion. J Biol Chem. 2004 Mar 5;279(10):8856-61. doi: 10.1074/jbc.M306422200. Epub 2003 Dec 18.
• [18] 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.
• [19] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [20] Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid-induced liver hypertrophy. Hepatology. 2009 Mar;49(3):979-88. doi: 10.1002/hep.22712.
• [21] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [22] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.
• [23] 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.
• [24] Adaptive homeostasis of the vitamin D-vitamin D nuclear receptor axis in 8-methoxypsoralen-induced hepatotoxicity. Toxicol Appl Pharmacol. 2019 Jan 1;362:150-158. doi: 10.1016/j.taap.2018.11.002. Epub 2018 Nov 10.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [27] Activation of human nuclear receptors by perfluoroalkylated substances (PFAS). Toxicol In Vitro. 2020 Feb;62:104700. doi: 10.1016/j.tiv.2019.104700. Epub 2019 Oct 30.
• [28] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [29] The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth. Free Radic Biol Med. 2009 Jan 15;46(2):220-31.
• [30] RNA-protein correlation of liver toxicity markers in HepaRG cells. EXCLI J. 2020 Jan 17;19:135-153. doi: 10.17179/excli2019-2005. eCollection 2020.
• [31] 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.
• [32] No activation of human pregnane X receptor by hyperforin-related phloroglucinols. J Pharmacol Exp Ther. 2014 Mar;348(3):393-400.
• [33] Baohuoside I inhibits FXR signaling pathway to interfere with bile acid homeostasis via targeting ER degradation. Cell Biol Toxicol. 2023 Aug;39(4):1215-1235. doi: 10.1007/s10565-022-09737-x. Epub 2022 Jul 8.
• [34] 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.
• [35] Oxysterol 7 alpha-hydroxylase activity by cholesterol 7 alpha-hydroxylase (CYP7A). J Biol Chem. 2000 Nov 3;275(44):34046-53. doi: 10.1074/jbc.M002663200.
• [36] 24-hydroxycholesterol is a substrate for hepatic cholesterol 7alpha-hydroxylase (CYP7A). J Lipid Res. 2000 Oct;41(10):1629-39.