Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6WNFU8)

• DOT Name: Carbonic anhydrase 12 (CA12)
• Synonyms: EC 4.2.1.1; Carbonate dehydratase XII; Carbonic anhydrase XII; CA-XII; Tumor antigen HOM-RCC-3.1.3
• Gene Name: CA12
• Related Disease: Isolated hyperchlorhidrosis
• UniProt ID: CAH12_HUMAN
• PDB ID: 1JCZ; 1JD0; 4HT2; 4KP5; 4KP8; 4Q0L; 4QJ0; 4QJO; 4QJW; 4WW8; 5LL5; 5LL9; 5LLO; 5LLP; 5MSA; 5MSB; 6G5L; 6G7A; 6QN0; 6QNG; 6QNL; 6R6Y; 6R71; 6RPS; 6T5P; 6T5Q; 7PP9; 7PUU; 7PUV; 7PUW
• EC Number: 4.2.1.1
• Pfam ID: PF00194
• Sequence:
  MPRRSLHAAAVLLLVILKEQPSSPAPVNGSKWTYFGPDGENSWSKKYPSCGGLLQSPIDL
  HSDILQYDASLTPLEFQGYNLSANKQFLLTNNGHSVKLNLPSDMHIQGLQSRYSATQLHL
  HWGNPNDPHGSEHTVSGQHFAAELHIVHYNSDLYPDASTASNKSEGLAVLAVLIEMGSFN
  PSYDKIFSHLQHVKYKGQEAFVPGFNIEELLPERTAEYYRYRGSLTTPPCNPTVLWTVFR
  NPVQISQEQLLALETALYCTHMDDPSPREMINNFRQVQKFDERLVYTSFSQVQVCTAAGL
  SLGIILSLALAGILGICIVVVVSIWLFRRKSIKKGDNKGVIYKPATKMETEAHA
• Function: Reversible hydration of carbon dioxide.
• Tissue Specificity: Highly expressed in colon, kidney, prostate, intestine and activated lymphocytes. Expressed at much higher levels in the renal cell cancers than in surrounding normal kidney tissue. Moderately expressed in pancreas, ovary and testis. Expressed in sweat glands and bronchiolar epithelium .
• KEGG Pathway:
  Nitrogen metabolism (hsa00910)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Reversible hydration of carbon dioxide (R-HSA-1475029)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isolated hyperchlorhidrosis	DISSVF3S	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Carbonic anhydrase 12 (CA12).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Carbonic anhydrase 12 (CA12).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Carbonic anhydrase 12 (CA12).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carbonic anhydrase 12 (CA12).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Carbonic anhydrase 12 (CA12).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Carbonic anhydrase 12 (CA12).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Carbonic anhydrase 12 (CA12).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Carbonic anhydrase 12 (CA12).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Carbonic anhydrase 12 (CA12).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Carbonic anhydrase 12 (CA12).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Carbonic anhydrase 12 (CA12).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Carbonic anhydrase 12 (CA12).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Carbonic anhydrase 12 (CA12).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Carbonic anhydrase 12 (CA12).	[15]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Carbonic anhydrase 12 (CA12).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Carbonic anhydrase 12 (CA12).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Carbonic anhydrase 12 (CA12).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Carbonic anhydrase 12 (CA12).	[18]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Carbonic anhydrase 12 (CA12).	[19]
Estrone	DM5T6US	Approved	Estrone increases the expression of Carbonic anhydrase 12 (CA12).	[15]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Carbonic anhydrase 12 (CA12).	[20]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of Carbonic anhydrase 12 (CA12).	[15]
Topiramate	DM82Z30	Approved	Topiramate decreases the activity of Carbonic anhydrase 12 (CA12).	[21]
Acetazolamide	DM1AF5U	Approved	Acetazolamide decreases the activity of Carbonic anhydrase 12 (CA12).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Carbonic anhydrase 12 (CA12).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Carbonic anhydrase 12 (CA12).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Carbonic anhydrase 12 (CA12).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Carbonic anhydrase 12 (CA12).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Carbonic anhydrase 12 (CA12).	[26]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL increases the expression of Carbonic anhydrase 12 (CA12).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Carbonic anhydrase 12 (CA12).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Carbonic anhydrase 12 (CA12).	[28]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Hydroxydimethylarsine Oxide increases the expression of Carbonic anhydrase 12 (CA12).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Carbonic anhydrase 12 (CA12).	[7]

References

• [1] Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII. Am J Hum Genet. 2010 Nov 12;87(5):713-20. doi: 10.1016/j.ajhg.2010.10.008. Epub 2010 Oct 28.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [7] Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure. Environ Health Perspect. 2020 Jun;128(6):67015. doi: 10.1289/EHP6263. Epub 2020 Jun 30.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line. Physiol Genomics. 2004 Apr 13;17(2):122-9. doi: 10.1152/physiolgenomics.00002.2003.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [13] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [16] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [17] 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.
• [18] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [19] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [20] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [21] Design, synthesis, and biological evaluation of novel carbohydrate-based sulfamates as carbonic anhydrase inhibitors. J Med Chem. 2011 Mar 10;54(5):1481-9.
• [22] Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors. J Med Chem. 2011 Oct 13;54(19):6905-18.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [25] Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands. Toxicol Lett. 2011 Oct 10;206(2):178-88.
• [26] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [27] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [29] Identification of interspecies concordance of mechanisms of arsenic-induced bladder cancer. Toxicol In Vitro. 2007 Dec;21(8):1513-29. doi: 10.1016/j.tiv.2007.06.021. Epub 2007 Jul 21.