Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1MTYUH)

• DOT Name: Ammonium transporter Rh type C (RHCG)
• Synonyms: Rh glycoprotein kidney; Rhesus blood group family type C glycoprotein; Rh family type C glycoprotein; Rh type C glycoprotein; Tumor-related protein DRC2
• Gene Name: RHCG
• UniProt ID: RHCG_HUMAN
• PDB ID: 3HD6
• Pfam ID: PF00909
• Sequence:
  MAWNTNLRWRLPLTCLLLQVIMVILFGVFVRYDFEADAHWWSERTHKNLSDMENEFYYRY
  PSFQDVHVMVFVGFGFLMTFLQRYGFSAVGFNFLLAAFGIQWALLMQGWFHFLQDRYIVV
  GVENLINADFCVASVCVAFGAVLGKVSPIQLLIMTFFQVTLFAVNEFILLNLLKVKDAGG
  SMTIHTFGAYFGLTVTRILYRRNLEQSKERQNSVYQSDLFAMIGTLFLWMYWPSFNSAIS
  YHGDSQHRAAINTYCSLAACVLTSVAISSALHKKGKLDMVHIQNATLAGGVAVGTAAEMM
  LMPYGALIIGFVCGIISTLGFVYLTPFLESRLHIQDTCGINNLHGIPGIIGGIVGAVTAA
  SASLEVYGKEGLVHSFDFQGFNGDWTARTQGKFQIYGLLVTLAMALMGGIIVGLILRLPF
  WGQPSDENCFEDAVYWEMPEGNSTVYIPEDPTFKPSGPSVPSVPMVSPLPMASSVPLVP
• Function: Ammonium transporter involved in the maintenance of acid-base homeostasis. Transports ammonium and its related derivative methylammonium across the plasma membrane of epithelial cells likely contributing to renal transepithelial ammonia transport and ammonia metabolism. Postulated to primarily mediate an electroneutral bidirectional transport of NH3 ammonia species according to a mechanism that implies interaction of an NH4(+) ion with acidic residues of the pore entry followed by dissociation of NH4(+) into NH3 and H(+). As a result NH3 transits through the central pore and is protonated on the extracellular side reforming NH4(+). May act as a CO2 channel providing for renal acid secretion.
• Tissue Specificity: Expressed in brain, testis, placenta, pancreas, esophagus and prostate. Expressed in squamous epithelial tissues (at protein level). Expressed in kidney.
• Reactome Pathway: Rhesus glycoproteins mediate ammonium transport. (R-HSA-444411)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Ammonia	DMOEVK6	Approved	Ammonium transporter Rh type C (RHCG) affects the metabolism of Ammonia.	[8]
3-iodothyronamine	DM3L0F8	Investigative	Ammonium transporter Rh type C (RHCG) affects the uptake of 3-iodothyronamine.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ammonium transporter Rh type C (RHCG).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ammonium transporter Rh type C (RHCG).	[2]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Ammonium transporter Rh type C (RHCG).	[3]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ammonium transporter Rh type C (RHCG).	[5]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ammonium transporter Rh type C (RHCG).	[6]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 decreases the expression of Ammonium transporter Rh type C (RHCG).	[7]

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 Ammonium transporter Rh type C (RHCG).	[4]

References

• [1] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [2] 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.
• [3] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [4] 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.
• [5] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [6] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [7] Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact. 2009 Feb 12;177(3):173-80. doi: 10.1016/j.cbi.2008.10.051. Epub 2008 Nov 6.
• [8] Expression of the ammonia transporter, rh C glycoprotein, in normal and neoplastic human kidney. J Am Soc Nephrol. 2006 Oct;17(10):2670-9. doi: 10.1681/ASN.2006020160. Epub 2006 Aug 23.
• [9] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.