Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT72ZAWS)

• DOT Name: Solute carrier family 22 member 12 (SLC22A12)
• Synonyms: Organic anion transporter 4-like protein; Renal-specific transporter; RST; Urate anion exchanger 1; URAT1; Urate:anion antiporter SLC22A12
• Gene Name: SLC22A12
• Related Disease:
  Hypouricemia, renal 1
  Hereditary renal hypouricemia
• UniProt ID: S22AC_HUMAN
• Pfam ID: PF07690
• Sequence:
  MAFSELLDLVGGLGRFQVLQTMALMVSIMWLCTQSMLENFSAAVPSHRCWAPLLDNSTAQ
  ASILGSLSPEALLAISIPPGPNQRPHQCRRFRQPQWQLLDPNATATSWSEADTEPCVDGW
  VYDRSIFTSTIVAKWNLVCDSHALKPMAQSIYLAGILVGAAACGPASDRFGRRLVLTWSY
  LQMAVMGTAAAFAPAFPVYCLFRFLLAFAVAGVMMNTGTLLMEWTAARARPLVMTLNSLG
  FSFGHGLTAAVAYGVRDWTLLQLVVSVPFFLCFLYSWWLAESARWLLTTGRLDWGLQELW
  RVAAINGKGAVQDTLTPEVLLSAMREELSMGQPPASLGTLLRMPGLRFRTCISTLCWFAF
  GFTFFGLALDLQALGSNIFLLQMFIGVVDIPAKMGALLLLSHLGRRPTLAASLLLAGLCI
  LANTLVPHEMGALRSALAVLGLGGVGAAFTCITIYSSELFPTVLRMTAVGLGQMAARGGA
  ILGPLVRLLGVHGPWLPLLVYGTVPVLSGLAALLLPETQSLPLPDTIQDVQNQAVKKATH
  GTLGNSVLKSTQF
• Function: Electroneutral antiporter that translocates urate across the apical membrane of proximal tubular cells in exchange for monovalent organic or inorganic anions. Involved in renal reabsorption of urate and helps maintaining blood levels of uric acid. Mediates urate uptake by an exchange with organic anions such as (S)-lactate and nicotinate, and inorganic anion Cl(-). Other inorganic anions such as Br(-), I(-) and NO3(-) may also act as counteranions that exchange for urate. Also mediates orotate tubular uptake coupled with nicotinate efflux and to a lesser extent with lactate efflux, therefore displaying a potential role in orotate renal reabsorption. Orotate transport is Cl(-)-dependent.
• Tissue Specificity: Detected in kidney (at protein level). Detected in fetal and adult kidney. Detected in epithelial cells of proximal tubules in renal cortex.
• Reactome Pathway:
  Defective SLC22A12 causes renal hypouricemia 1 (RHUC1) (R-HSA-5619071)
  Organic anion transport (R-HSA-561048)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypouricemia, renal 1	DISGG7SU	Strong	Autosomal recessive	[1]
Hereditary renal hypouricemia	DISURZ91	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Oxypurinol	DMURH4X	Phase 2/3	Solute carrier family 22 member 12 (SLC22A12) increases the uptake of Oxypurinol.	[7]
[3H]estrone-3-sulphate	DMGPF0N	Investigative	Solute carrier family 22 member 12 (SLC22A12) increases the uptake of [3H]estrone-3-sulphate.	[8]

3 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 Solute carrier family 22 member 12 (SLC22A12).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Solute carrier family 22 member 12 (SLC22A12).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Solute carrier family 22 member 12 (SLC22A12).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzbromarone	DMC3YUA	Approved	Benzbromarone decreases the activity of Solute carrier family 22 member 12 (SLC22A12).	[5]
Probenecid	DMMFWOJ	Approved	Probenecid affects the activity of Solute carrier family 22 member 12 (SLC22A12).	[1]
Pyrazinamide	DM4IF32	Approved	Pyrazinamide affects the activity of Solute carrier family 22 member 12 (SLC22A12).	[1]
Erythropoietin	DM3R8YL	Investigative	Erythropoietin decreases the expression of Solute carrier family 22 member 12 (SLC22A12).	[5]

References

• [1] Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004 Jan;15(1):164-73. doi: 10.1097/01.asn.0000105320.04395.d0.
• [2] URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews. Nephrol Dial Transplant. 2011 Jul;26(7):2175-81. doi: 10.1093/ndt/gfq722. Epub 2010 Dec 9.
• [3] 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.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Effect of losartan and benzbromarone on the level of human urate transporter 1 mRNA. Arzneimittelforschung. 2010;60(4):186-8. doi: 10.1055/s-0031-1296271.
• [6] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [7] Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. Drug Metab Dispos. 2005 Dec;33(12):1791-5.
• [8] Lack of interaction of the fluorosurfactant C6O4 with human renal transporters: In vitro/in silico analysis. Toxicology. 2022 Jun 30;476:153257. doi: 10.1016/j.tox.2022.153257. Epub 2022 Jul 12.