Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIJ65J4)

• DOT Name: Complement component C8 alpha chain (C8A)
• Synonyms: Complement component 8 subunit alpha
• Gene Name: C8A
• Related Disease:
  Complement deficiency
  Meningitis
  Type I complement component 8 deficiency
  Immunodeficiency
  Myocardial infarction
• UniProt ID: CO8A_HUMAN
• PDB ID: 2QOS; 2QQH; 2RD7; 3OJY; 6H03; 6H04; 7NYC; 7NYD; 8B0F; 8B0G; 8B0H
• Pfam ID: PF21195 ; PF00057 ; PF01823 ; PF00090
• Sequence:
  MFAVVFFILSLMTCQPGVTAQEKVNQRVRRAATPAAVTCQLSNWSEWTDCFPCQDKKYRH
  RSLLQPNKFGGTICSGDIWDQASCSSSTTCVRQAQCGQDFQCKETGRCLKRHLVCNGDQD
  CLDGSDEDDCEDVRAIDEDCSQYEPIPGSQKAALGYNILTQEDAQSVYDASYYGGQCETV
  YNGEWRELRYDSTCERLYYGDDEKYFRKPYNFLKYHFEALADTGISSEFYDNANDLLSKV
  KKDKSDSFGVTIGIGPAGSPLLVGVGVSHSQDTSFLNELNKYNEKKFIFTRIFTKVQTAH
  FKMRKDDIMLDEGMLQSLMELPDQYNYGMYAKFINDYGTHYITSGSMGGIYEYILVIDKA
  KMESLGITSRDITTCFGGSLGIQYEDKINVGGGLSGDHCKKFGGGKTERARKAMAVEDII
  SRVRGGSSGWSGGLAQNRSTITYRSWGRSLKYNPVVIDFEMQPIHEVLRHTSLGPLEAKR
  QNLRRALDQYLMEFNACRCGPCFNNGVPILEGTSCRCQCRLGSLGAACEQTQTEGAKADG
  SWSCWSSWSVCRAGIQERRRECDNPAPQNGGASCPGRKVQTQAC
• Function: Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells. C8A inserts into the target membrane, but does not form pores by itself.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Regulation of actin cytoskeleton (hsa04810)
  Prion disease (hsa05020)
  Amoebiasis (hsa05146)
  Coro.virus disease - COVID-19 (hsa05171)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Regulation of Complement cascade (R-HSA-977606)
  Terminal pathway of complement (R-HSA-166665)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complement deficiency	DISGN469	Strong	Biomarker	[1]
Meningitis	DISQABAA	Strong	Biomarker	[1]
Type I complement component 8 deficiency	DIS5ZBK1	Strong	Autosomal recessive	[2]
Immunodeficiency	DIS093I0	Limited	Biomarker	[1]
Myocardial infarction	DIS655KI	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Complement component C8 alpha chain (C8A).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Complement component C8 alpha chain (C8A).	[13]

12 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 Complement component C8 alpha chain (C8A).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement component C8 alpha chain (C8A).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complement component C8 alpha chain (C8A).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Complement component C8 alpha chain (C8A).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Complement component C8 alpha chain (C8A).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Complement component C8 alpha chain (C8A).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Complement component C8 alpha chain (C8A).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Complement component C8 alpha chain (C8A).	[11]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Complement component C8 alpha chain (C8A).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Complement component C8 alpha chain (C8A).	[12]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Complement component C8 alpha chain (C8A).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Complement component C8 alpha chain (C8A).	[14]

References

• [1] Genetic basis of human complement C8 alpha-gamma deficiency.J Immunol. 1998 Oct 1;161(7):3762-6.
• [2] A Point Mutation Creating a 3' Splice Site in C8A Is a Predominant Cause of C8- Deficiency in African Americans. J Immunol. 2020 Sep 15;205(6):1535-1539. doi: 10.4049/jimmunol.2000272. Epub 2020 Aug 7.
• [3] Time course of complement activation and inhibitor expression after ischemic injury of rat myocardium.Am J Pathol. 1994 Jun;144(6):1357-68.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [13] 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.
• [14] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.