Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW4A4Q0)

• DOT Name: NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8)
• Synonyms: Complex I-ASHI; CI-ASHI; NADH-ubiquinone oxidoreductase ASHI subunit
• Gene Name: NDUFB8
• Related Disease:
  Acute kidney injury
  Alzheimer disease
  Fatal familial insomnia
  Mitochondrial complex I deficiency, nuclear type 1
  Mitochondrial disease
  Skin disease
  Leigh syndrome
  Mitochondrial complex 1 deficiency, nuclear type 32
  Mitochondrial complex I deficiency
  Leigh syndrome with cardiomyopathy
  Cervical cancer
  Cervical carcinoma
• UniProt ID: NDUB8_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF05821
• Sequence:
  MAVARAGVLGVQWLQRASRNVMPLGARTASHMTKDMFPGPYPRTPEERAAAAKKYNMRVE
  DYEPYPDDGMGYGDYPKLPDRSQHERDPWYSWDQPGLRLNWGEPMHWHLDMYNRNRVDTS
  PTPVSWHVMCMQLFGFLAFMIFMCWVGDVYPVYQPVGPKQYPYNNLYLERGGDPSKEPER
  VVHYEI
• Function: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Respiratory electron transport (R-HSA-611105)
  Complex I biogenesis (R-HSA-6799198)
  Mitochondrial protein import (R-HSA-1268020)
• BioCyc Pathway: MetaCyc:HS09335-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute kidney injury	DISXZG0T	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Fatal familial insomnia	DIS1FL1J	Strong	Altered Expression	[3]
Mitochondrial complex I deficiency, nuclear type 1	DISCPLX4	Strong	Autosomal recessive	[4]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[4]
Skin disease	DISDW8R6	Strong	Biomarker	[5]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[6]
Mitochondrial complex 1 deficiency, nuclear type 32	DISDHFT7	Moderate	Autosomal recessive	[7]
Mitochondrial complex I deficiency	DIS13M7V	moderate	Genetic Variation	[4]
Leigh syndrome with cardiomyopathy	DIS2UELC	Supportive	Autosomal recessive	[4]
Cervical cancer	DISFSHPF	Limited	Biomarker	[8]
Cervical carcinoma	DIST4S00	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8) affects the response to substance of Josamycin.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[15]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[16]
Telbivudine	DMSWUGE	Approved	Telbivudine decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[22]

1 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 increases the methylation of NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial (NDUFB8).	[19]

References

• [1] Persistent disruption of mitochondrial homeostasis after acute kidney injury.Am J Physiol Renal Physiol. 2012 Apr 1;302(7):F853-64. doi: 10.1152/ajprenal.00035.2011. Epub 2011 Dec 7.
• [2] Reduced levels of mitochondrial complex I subunit NDUFB8 and linked complex I + III oxidoreductase activity in the TgCRND8 mouse model of Alzheimer's disease.J Alzheimers Dis. 2014;39(2):347-55. doi: 10.3233/JAD-131499.
• [3] Fatal familial insomnia: mitochondrial and protein synthesis machinery decline in the mediodorsal thalamus.Brain Pathol. 2017 Jan;27(1):95-106. doi: 10.1111/bpa.12408. Epub 2016 Aug 2.
• [4] NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh-like Encephalomyopathy. Am J Hum Genet. 2018 Mar 1;102(3):460-467. doi: 10.1016/j.ajhg.2018.01.008. Epub 2018 Feb 8.
• [5] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [6] 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.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] PTEN and NDUFB8 aberrations in cervical cancer tissue.Adv Exp Med Biol. 2007;599:31-6. doi: 10.1007/978-0-387-71764-7_5.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [11] 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.
• [12] 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.
• [13] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [14] PGK1 induction by a hydrogen peroxide treatment is suppressed by antioxidants in human colon carcinoma cells. Biosci Biotechnol Biochem. 2008 Jul;72(7):1799-808. doi: 10.1271/bbb.80079. Epub 2008 Jul 7.
• [15] 9-Tetrahydrocannabinol leads to endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo trophoblasts. Reprod Toxicol. 2019 Aug;87:21-31. doi: 10.1016/j.reprotox.2019.04.008. Epub 2019 May 1.
• [16] Pod-based menthol and tobacco flavored e-cigarettes cause mitochondrial dysfunction in lung epithelial cells. Toxicol Lett. 2020 Oct 15;333:303-311. doi: 10.1016/j.toxlet.2020.08.003. Epub 2020 Aug 9.
• [17] Insights into the mechanisms of telbivudine-induced myopathy associated with mitochondrial dysfunction. Chem Biol Interact. 2023 Sep 25;383:110692. doi: 10.1016/j.cbi.2023.110692. Epub 2023 Sep 1.
• [18] 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.
• [19] 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.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [23] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.