Details of Drug Off-Target (DOT)

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

• DOT Name: Beta,beta-carotene 15,15'-dioxygenase (BCO1)
• Synonyms: EC 1.13.11.63; Beta-carotene dioxygenase 1; Beta-carotene oxygenase 1
• Gene Name: BCO1
• Related Disease: Hereditary hypercarotenemia and vitamin A deficiency
• UniProt ID: BCDO1_HUMAN
• EC Number: 1.13.11.63
• Pfam ID: PF03055
• Sequence:
  MDIIFGRNRKEQLEPVRAKVTGKIPAWLQGTLLRNGPGMHTVGESRYNHWFDGLALLHSF
  TIRDGEVYYRSKYLRSDTYNTNIEANRIVVSEFGTMAYPDPCKNIFSKAFSYLSHTIPDF
  TDNCLINIMKCGEDFYATSETNYIRKINPQTLETLEKVDYRKYVAVNLATSHPHYDEAGN
  VLNMGTSIVEKGKTKYVIFKIPATVPEGKKQGKSPWKHTEVFCSIPSRSLLSPSYYHSFG
  VTENYVIFLEQPFRLDILKMATAYIRRMSWASCLAFHREEKTYIHIIDQRTRQPVQTKFY
  TDAMVVFHHVNAYEEDGCIVFDVIAYEDNSLYQLFYLANLNQDFKENSRLTSVPTLRRFA
  VPLHVDKNAEVGTNLIKVASTTATALKEEDGQVYCQPEFLYEGLELPRVNYAHNGKQYRY
  VFATGVQWSPIPTKIIKYDILTKSSLKWREDDCWPAEPLFVPAPGAKDEDDGVILSAIVS
  TDPQKLPFLLILDAKSFTELARASVDVDMHMDLHGLFITDMDWDTKKQAASEEQRDRASD
  CHGAPLT
• Function: Symmetrically cleaves beta-carotene into two molecules of retinal using a dioxygenase mechanism.
• Tissue Specificity: Highly expressed in retinal pigment epithelium. Also expressed in kidney, testis, liver, brain, small intestine and colon.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Retinoid metabolism and transport (R-HSA-975634)
• BioCyc Pathway: MetaCyc:HS06050-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
Hereditary hypercarotenemia and vitamin A deficiency	DISP5MQC	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[5]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[3]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[9]
Ro 41-5253	DMSJLWP	Investigative	Ro 41-5253 increases the expression of Beta,beta-carotene 15,15'-dioxygenase (BCO1).	[3]

References

• [1] Loss-of-function mutation in carotenoid 15,15'-monooxygenase identified in a patient with hypercarotenemia and hypovitaminosis A. J Nutr. 2007 Nov;137(11):2346-50. doi: 10.1093/jn/137.11.2346.
• [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] Beta-Carotene conversion into vitamin A in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2005 Oct;46(10):3562-9.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [6] 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.
• [7] 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.
• [8] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.