Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKA2AL6)

• DOT Name: Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (DHDH)
• Synonyms: EC 1.3.1.20; D-xylose 1-dehydrogenase; D-xylose-NADP dehydrogenase; EC 1.1.1.179; Dimeric dihydrodiol dehydrogenase; Hum2DD
• Gene Name: DHDH
• Related Disease:
  Gastric neoplasm
  Adult germ cell tumor
  Breast carcinoma
  Carcinoma
  Esophageal squamous cell carcinoma
  Germ cell tumor
  Germ cell tumour
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate neoplasm
  Cervical cancer
  Human papillomavirus infection
  Non-small-cell lung cancer
• UniProt ID: DHDH_HUMAN
• EC Number: 1.1.1.179; 1.3.1.20
• Pfam ID: PF01408 ; PF02894
• Sequence:
  MALRWGIVSVGLISSDFTAVLQTLPRSEHQVVAVAARDLSRAKEFAQKHDIPKAYGSYEE
  LAKDPSVEVAYIGTQHPQHKAAVMLCLAAGKAVLCEKPTGVNAAEVREMVAEARSRALFL
  MEAIWTRFFPASEALRSVLAQGTLGDLRVARAEFGKNLIHVPRAVDRAQAGGALLDIGIY
  CVQFTSMVFGGQKPEKISVVGRRHETGVDDTVTVLLQYPGEVHGSFTCSITVQLSNTASV
  SGTKGMVQLLNPCWCPTELVVKGEHKEFPLPPVPKDCNFDNGAGMSYEAKHVWECLRKGM
  KESPVIPLSESELLADILEEVRKAIGVTFPQDKR
• Tissue Specificity: Small intestine.
• KEGG Pathway:
  Pentose and glucuro.te interconversions (hsa00040)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Metabolic pathways (hsa01100)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric neoplasm	DISOKN4Y	Definitive	Altered Expression	[1]
Adult germ cell tumor	DISJUCQ7	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Germ cell tumor	DIS62070	Strong	Altered Expression	[2]
Germ cell tumour	DISOF3TK	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[9]
Human papillomavirus infection	DISX61LX	Limited	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[10]

5 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 Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (DHDH).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (DHDH).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (DHDH).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (DHDH).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (DHDH).	[15]

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 decreases the methylation of Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase (DHDH).	[16]

References

• [1] Overexpression of dihydrodiol dehydrogenase as a prognostic marker in resected gastric cancer patients.Dig Dis Sci. 2009 Feb;54(2):342-7. doi: 10.1007/s10620-008-0350-7. Epub 2008 Jul 5.
• [2] Dihydrodiol dehydrogenases regulate the generation of reactive oxygen species and the development of cisplatin resistance in human ovarian carcinoma cells.Cancer Chemother Pharmacol. 2008 May;61(6):979-87. doi: 10.1007/s00280-007-0554-0. Epub 2007 Jul 28.
• [3] Stable expression of rat dihydrodiol dehydrogenase (AKR1C9) in human breast MCF-7 cells results in the formation of PAH-o-quinones and enzyme mediated cell death.Chem Res Toxicol. 2001 Jul;14(7):856-62. doi: 10.1021/tx0100035.
• [4] Dihydrodiol dehydrogenase in drug resistance and sensitivity of human carcinomas.Cancer Chemother Pharmacol. 2007 Apr;59(5):697-702. doi: 10.1007/s00280-006-0351-1. Epub 2006 Sep 29.
• [5] Inverse expression of dihydrodiol dehydrogenase and glutathione-S-transferase in patients with esophageal squamous cell carcinoma.Int J Cancer. 2004 Aug 20;111(2):246-51. doi: 10.1002/ijc.11650.
• [6] Reduction of dihydrodiol dehydrogenase expression in resected hepatocellular carcinoma.Oncol Rep. 2003 Mar-Apr;10(2):271-6.
• [7] Ileal interposition coupled with duodenal diverted sleeve gastrectomy versus standard medical treatment in type 2 diabetes mellitus obese patients: long-term results of a case-control study.Surg Endosc. 2019 May;33(5):1553-1563. doi: 10.1007/s00464-018-6443-2. Epub 2018 Sep 17.
• [8] Xenobiotic-metabolizing gene variants, pesticide use, and the risk of prostate cancer.Pharmacogenet Genomics. 2011 Oct;21(10):615-23. doi: 10.1097/FPC.0b013e3283493a57.
• [9] Infection of human papillomavirus and overexpression of dihydrodiol dehydrogenase in uterine cervical cancer.Gynecol Oncol. 2006 Aug;102(2):173-81. doi: 10.1016/j.ygyno.2005.12.009. Epub 2006 Jan 20.
• [10] Overexpression of dihydrodiol dehydrogenase as a prognostic marker of non-small cell lung cancer.Cancer Res. 2001 Mar 15;61(6):2727-31.
• [11] 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.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [16] 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.