Details of Drug Off-Target (DOT)

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

• DOT Name: Biliverdin reductase A (BLVRA)
• Synonyms: BVR A; EC 1.3.1.24; Biliverdin-IX alpha-reductase
• Gene Name: BLVRA
• Related Disease: Hyperbiliverdinemia
• UniProt ID: BIEA_HUMAN
• PDB ID: 2H63
• EC Number: 1.3.1.24
• Pfam ID: PF09166 ; PF01408
• Sequence:
  MNAEPERKFGVVVVGVGRAGSVRMRDLRNPHPSSAFLNLIGFVSRRELGSIDGVQQISLE
  DALSSQEVEVAYICSESSSHEDYIRQFLNAGKHVLVEYPMTLSLAAAQELWELAEQKGKV
  LHEEHVELLMEEFAFLKKEVVGKDLLKGSLLFTAGPLEEERFGFPAFSGISRLTWLVSLF
  GELSLVSATLEERKEDQYMKMTVCLETEKKSPLSWIEEKGPGLKRNRYLSFHFKSGSLEN
  VPNVGVNKNIFLKDQNIFVQKLLGQFSEKELAAEKKRILHCLGLAEEIQKYCCSRK
• Function: Reduces the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor. Uses the reactants NADH or NADPH depending on the pH; NADH is used at the acidic pH range (6-6.9) and NADPH at the alkaline range (8.5-8.7). NADPH, however, is the probable reactant in biological systems.
• Tissue Specificity: Liver.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Heme degradation (R-HSA-189483)
• BioCyc Pathway: MetaCyc:HS02928-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
Hyperbiliverdinemia	DIS0ZA9V	Supportive	Autosomal dominant	[1]

17 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 Biliverdin reductase A (BLVRA).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Biliverdin reductase A (BLVRA).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Biliverdin reductase A (BLVRA).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Biliverdin reductase A (BLVRA).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Biliverdin reductase A (BLVRA).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Biliverdin reductase A (BLVRA).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Biliverdin reductase A (BLVRA).	[8]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Biliverdin reductase A (BLVRA).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Biliverdin reductase A (BLVRA).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Biliverdin reductase A (BLVRA).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Biliverdin reductase A (BLVRA).	[12]
Taurocholic acid	DM2LZ8F	Phase 1/2	Taurocholic acid increases the expression of Biliverdin reductase A (BLVRA).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Biliverdin reductase A (BLVRA).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Biliverdin reductase A (BLVRA).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Biliverdin reductase A (BLVRA).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Biliverdin reductase A (BLVRA).	[19]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Biliverdin reductase A (BLVRA).	[20]

2 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 Biliverdin reductase A (BLVRA).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Biliverdin reductase A (BLVRA).	[16]

References

• [1] A homozygous nonsense mutation (c.214C->A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis. J Med Genet. 2011 Apr;48(4):219-25. doi: 10.1136/jmg.2009.074567. Epub 2011 Jan 28.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [10] Identification of potential biomarkers for predicting acute dermal irritation by proteomic analysis. J Appl Toxicol. 2011 Nov;31(8):762-72.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Role of vitamin C transporters and biliverdin reductase in the dual pro-oxidant and anti-oxidant effect of biliary compounds on the placental-fetal unit in cholestasis during pregnancy. Toxicol Appl Pharmacol. 2008 Oct 15;232(2):327-36.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology. 2020 Nov;444:152582. doi: 10.1016/j.tox.2020.152582. Epub 2020 Sep 6.
• [20] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.