Details of Drug Off-Target (DOT)

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

• DOT Name: NADPH--cytochrome P450 reductase (POR)
• Synonyms: CPR; P450R; EC 1.6.2.4
• Gene Name: POR
• Related Disease:
  Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis
  Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency
  Antley-Bixler syndrome
• UniProt ID: NCPR_HUMAN
• PDB ID: 1B1C; 3FJO; 3QE2; 3QFC; 3QFR; 3QFS; 3QFT; 5EMN; 5FA6
• EC Number: 1.6.2.4
• Pfam ID: PF00667 ; PF00258 ; PF00175
• Sequence:
  MGDSHVDTSSTVSEAVAEEVSLFSMTDMILFSLIVGLLTYWFLFRKKKEEVPEFTKIQTL
  TSSVRESSFVEKMKKTGRNIIVFYGSQTGTAEEFANRLSKDAHRYGMRGMSADPEEYDLA
  DLSSLPEIDNALVVFCMATYGEGDPTDNAQDFYDWLQETDVDLSGVKFAVFGLGNKTYEH
  FNAMGKYVDKRLEQLGAQRIFELGLGDDDGNLEEDFITWREQFWPAVCEHFGVEATGEES
  SIRQYELVVHTDIDAAKVYMGEMGRLKSYENQKPPFDAKNPFLAAVTTNRKLNQGTERHL
  MHLELDISDSKIRYESGDHVAVYPANDSALVNQLGKILGADLDVVMSLNNLDEESNKKHP
  FPCPTSYRTALTYYLDITNPPRTNVLYELAQYASEPSEQELLRKMASSSGEGKELYLSWV
  VEARRHILAILQDCPSLRPPIDHLCELLPRLQARYYSIASSSKVHPNSVHICAVVVEYET
  KAGRINKGVATNWLRAKEPAGENGGRALVPMFVRKSQFRLPFKATTPVIMVGPGTGVAPF
  IGFIQERAWLRQQGKEVGETLLYYGCRRSDEDYLYREELAQFHRDGALTQLNVAFSREQS
  HKVYVQHLLKQDREHLWKLIEGGAHIYVCGDARNMARDVQNTFYDIVAELGAMEHAQAVD
  YIKKLMTKGRYSLDVWS
• Function: This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5.
• Reactome Pathway: Cytochrome P450 - arranged by substrate type (R-HSA-211897)
• BioCyc Pathway: MetaCyc:HS05140-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis	DISOXWIT	Definitive	Autosomal recessive	[1]
Congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency	DIS3HGIB	Strong	Autosomal recessive	[2]
Antley-Bixler syndrome	DISH25CS	Supportive	Autosomal dominant	[3]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	NADPH--cytochrome P450 reductase (POR) increases the abundance of Hydrogen peroxide.	[35]
Acetic Acid, Glacial	DM4SJ5Y	Approved	NADPH--cytochrome P450 reductase (POR) increases the metabolism of Acetic Acid, Glacial.	[37]

This DOT Affected the Drug Response of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	NADPH--cytochrome P450 reductase (POR) increases the response to substance of Irinotecan.	[36]
Paclitaxel	DMLB81S	Approved	NADPH--cytochrome P450 reductase (POR) increases the response to substance of Paclitaxel.	[36]
Mitomycin	DMH0ZJE	Approved	NADPH--cytochrome P450 reductase (POR) increases the response to substance of Mitomycin.	[36]
Docetaxel	DMDI269	Approved	NADPH--cytochrome P450 reductase (POR) increases the response to substance of Docetaxel.	[36]
Warfarin	DMJYCVW	Approved	NADPH--cytochrome P450 reductase (POR) affects the response to substance of Warfarin.	[38]
Tacrolimus	DMZ7XNQ	Approved	NADPH--cytochrome P450 reductase (POR) affects the response to substance of Tacrolimus.	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of NADPH--cytochrome P450 reductase (POR).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADPH--cytochrome P450 reductase (POR).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NADPH--cytochrome P450 reductase (POR).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NADPH--cytochrome P450 reductase (POR).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NADPH--cytochrome P450 reductase (POR).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADPH--cytochrome P450 reductase (POR).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the activity of NADPH--cytochrome P450 reductase (POR).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of NADPH--cytochrome P450 reductase (POR).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of NADPH--cytochrome P450 reductase (POR).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of NADPH--cytochrome P450 reductase (POR).	[13]
Menadione	DMSJDTY	Approved	Menadione increases the expression of NADPH--cytochrome P450 reductase (POR).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of NADPH--cytochrome P450 reductase (POR).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of NADPH--cytochrome P450 reductase (POR).	[16]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of NADPH--cytochrome P450 reductase (POR).	[17]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of NADPH--cytochrome P450 reductase (POR).	[16]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of NADPH--cytochrome P450 reductase (POR).	[18]
Anastrozole	DMNP60F	Approved	Anastrozole decreases the activity of NADPH--cytochrome P450 reductase (POR).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of NADPH--cytochrome P450 reductase (POR).	[20]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of NADPH--cytochrome P450 reductase (POR).	[6]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the activity of NADPH--cytochrome P450 reductase (POR).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of NADPH--cytochrome P450 reductase (POR).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of NADPH--cytochrome P450 reductase (POR).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of NADPH--cytochrome P450 reductase (POR).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of NADPH--cytochrome P450 reductase (POR).	[27]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of NADPH--cytochrome P450 reductase (POR).	[28]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of NADPH--cytochrome P450 reductase (POR).	[29]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of NADPH--cytochrome P450 reductase (POR).	[30]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of NADPH--cytochrome P450 reductase (POR).	[31]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX decreases the activity of NADPH--cytochrome P450 reductase (POR).	[32]
Hyperforin	DM2L3PE	Investigative	Hyperforin increases the expression of NADPH--cytochrome P450 reductase (POR).	[33]
THIOCTIC ACID	DMNFCXW	Investigative	THIOCTIC ACID decreases the activity of NADPH--cytochrome P450 reductase (POR).	[34]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	4-ANDROSTENE-3-17-DIONE increases the activity of NADPH--cytochrome P450 reductase (POR).	[19]

3 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 decreases the methylation of NADPH--cytochrome P450 reductase (POR).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of NADPH--cytochrome P450 reductase (POR).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NADPH--cytochrome P450 reductase (POR).	[25]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Identification of novel roles of the cytochrome p450 system in early embryogenesis: effects on vasculogenesis and retinoic Acid homeostasis. Mol Cell Biol. 2003 Sep;23(17):6103-16. doi: 10.1128/MCB.23.17.6103-6116.2003.
• [3] Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J Clin Endocrinol Metab. 2005 Jan;90(1):414-26. doi: 10.1210/jc.2004-0810. Epub 2004 Oct 13.
• [4] 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.
• [5] 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.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] StJohn's wort extracts and some of their constituents potently inhibit ultimate carcinogen formation from benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1. Cancer Res. 2003 Nov 15;63(22):8062-8.
• [11] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] 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.
• [14] NAD(P)H-dependent quinone oxidoreductase 1 (NQO1) and cytochrome P450 oxidoreductase (CYP450OR) differentially regulate menadione-mediated alterations in redox status, survival and metabolism in pancreatic beta-cells. Toxicol Lett. 2016 Nov 16;262:1-11.
• [15] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [16] 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.
• [17] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [18] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [19] Assessment of Five Pesticides as Endocrine-Disrupting Chemicals: Effects on Estrogen Receptors and Aromatase. Int J Environ Res Public Health. 2022 Feb 10;19(4):1959. doi: 10.3390/ijerph19041959.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Activity of NADPH-cytochrome P-450 reductase of the human heart, liver and lungs in the presence of (-)-epigallocatechin gallate, quercetin and resveratrol: an in vitro study. Basic Clin Pharmacol Toxicol. 2005 Aug;97(2):74-9.
• [22] 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.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] 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.
• [26] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [28] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [29] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [30] 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.
• [31] Instability of the human cytochrome p450 reductase A287P variant is the major contributor to its antley-bixler syndrome-like phenotype. J Biol Chem. 2016 Sep 23;291(39):20487-502.
• [32] Human NADPH-P450 oxidoreductase modulates the level of cytochrome P450 CYP2D6 holoprotein via haem oxygenase-dependent and -independent pathways. Biochem J. 2001 Jun 1;356(Pt 2):613-9.
• [33] No activation of human pregnane X receptor by hyperforin-related phloroglucinols. J Pharmacol Exp Ther. 2014 Mar;348(3):393-400.
• [34] Decrease in NADPH-cytochrome P450 reductase activity of the human heart, Liver and lungs in the presence of alpha-lipoic acid. Ann Nutr Metab. 2006;50(2):121-5.
• [35] Human recombinant cytochrome P450 enzymes display distinct hydrogen peroxide generating activities during substrate independent NADPH oxidase reactions. Toxicol Sci. 2014 Oct;141(2):344-52. doi: 10.1093/toxsci/kfu133. Epub 2014 Jul 24.
• [36] Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes. Int J Cancer. 2004 Sep 10;111(4):617-26. doi: 10.1002/ijc.20289.
• [37] Kinetics of trihalogenated acetic acid metabolism and isoform specificity in liver microsomes. Int J Toxicol. 2011 Oct;30(5):551-61. doi: 10.1177/1091581811414213. Epub 2011 Sep 20.
• [38] Influence of genetic polymorphisms in cytochrome P450 oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese. Eur J Clin Pharmacol. 2016 Nov;72(11):1327-1334. doi: 10.1007/s00228-016-2098-x. Epub 2016 Aug 4.
• [39] Single-nucleotide polymorphisms in P450 oxidoreductase and peroxisome proliferator-activated receptor- are associated with the development of new-onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenet Genomics. 2013 Dec;23(12):649-57. doi: 10.1097/FPC.0000000000000001.