Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC6I2SP)

• DOT Name: Dopamine beta-hydroxylase (DBH)
• Synonyms: EC 1.14.17.1; Dopamine beta-monooxygenase
• Gene Name: DBH
• Related Disease: Orthostatic hypotension 1
• UniProt ID: DOPO_HUMAN
• PDB ID: 4ZEL
• EC Number: 1.14.17.1
• Pfam ID: PF03712 ; PF01082 ; PF03351
• Sequence:
  MPALSRWASLPGPSMREAAFMYSTAVAIFLVILVAALQGSAPRESPLPYHIPLDPEGSLE
  LSWNVSYTQEAIHFQLLVRRLKAGVLFGMSDRGELENADLVVLWTDGDTAYFADAWSDQK
  GQIHLDPQQDYQLLQVQRTPEGLTLLFKRPFGTCDPKDYLIEDGTVHLVYGILEEPFRSL
  EAINGSGLQMGLQRVQLLKPNIPEPELPSDACTMEVQAPNIQIPSQETTYWCYIKELPKG
  FSRHHIIKYEPIVTKGNEALVHHMEVFQCAPEMDSVPHFSGPCDSKMKPDRLNYCRHVLA
  AWALGAKAFYYPEEAGLAFGGPGSSRYLRLEVHYHNPLVIEGRNDSSGIRLYYTAKLRRF
  NAGIMELGLVYTPVMAIPPRETAFILTGYCTDKCTQLALPPSGIHIFASQLHTHLTGRKV
  VTVLVRDGREWEIVNQDNHYSPHFQEIRMLKKVVSVHPGDVLITSCTYNTEDRELATVGG
  FGILEEMCVNYVHYYPQTQLELCKSAVDAGFLQKYFHLINRFNNEDVCTCPQASVSQQFT
  SVPWNSFNRDVLKALYSFAPISMHCNKSSAVRFQGEWNLQPLPKVISTLEEPTPQCPTSQ
  GRSPAGPTVVSIGGGKG
• Function: Catalyzes the hydroxylation of dopamine to noradrenaline (also known as norepinephrine), and is thus vital for regulation of these neurotransmitters.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Catecholamine biosynthesis (R-HSA-209905)
• BioCyc Pathway: MetaCyc:MONOMER66-381

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Orthostatic hypotension 1	DISOXVFG	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cocaine	DMSOX7I	Approved	Dopamine beta-hydroxylase (DBH) increases the response to substance of Cocaine.	[11]
Artesunate	DMR27C8	Approved	Dopamine beta-hydroxylase (DBH) increases the response to substance of Artesunate.	[12]
Lamotrigine	DM8SXYG	Approved	Dopamine beta-hydroxylase (DBH) increases the response to substance of Lamotrigine.	[13]

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 Dopamine beta-hydroxylase (DBH).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Dopamine beta-hydroxylase (DBH).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dopamine beta-hydroxylase (DBH).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dopamine beta-hydroxylase (DBH).	[4]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Dopamine beta-hydroxylase (DBH).	[5]
Levodopa	DMN3E57	Approved	Levodopa decreases the activity of Dopamine beta-hydroxylase (DBH).	[6]
Bromocriptine	DMVE3TK	Approved	Bromocriptine decreases the activity of Dopamine beta-hydroxylase (DBH).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dopamine beta-hydroxylase (DBH).	[7]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram decreases the activity of Dopamine beta-hydroxylase (DBH).	[8]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol increases the expression of Dopamine beta-hydroxylase (DBH).	[10]

References

• [1] Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency. Am J Med Genet. 2002 Mar 1;108(2):140-7.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Nicotine promotes cell proliferation via alpha7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells. Toxicol Appl Pharmacol. 2007 Jun 15;221(3):261-7. doi: 10.1016/j.taap.2007.04.002. Epub 2007 Apr 12.
• [6] Plasma dopamine beta hydroxylase (D.B.H.) activity in Parkinsonian patients under L-dopa, and 2-bromo-alpha-ergocriptine loading. J Neural Transm. 1979;46(1):71-8. doi: 10.1007/BF01243430.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Hypotension with anesthesia in disulfiram-treated patients. Anesthesiology. 1979 Oct;51(4):366-8.
• [9] 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.
• [10] Clioquinol inhibits dopamine--hydroxylase secretion and noradrenaline synthesis by affecting the redox status of ATOX1 and copper transport in human neuroblastoma SH-SY5Y cells. Arch Toxicol. 2021 Jan;95(1):135-148. doi: 10.1007/s00204-020-02894-0. Epub 2020 Oct 9.
• [11] A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia. Mol Psychiatry. 2000 Jan;5(1):56-63. doi: 10.1038/sj.mp.4000657.
• [12] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.
• [13] Genetic association study of treatment response with olanzapine/fluoxetine combination or lamotrigine in bipolar I depression. J Clin Psychiatry. 2010 May;71(5):599-605. doi: 10.4088/JCP.08m04632gre. Epub 2009 Dec 15.