Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC44CR6)

• DOT Name: Sorbitol dehydrogenase (SORD)
• Synonyms: SDH; EC 1.1.1.-; (R,R)-butanediol dehydrogenase; EC 1.1.1.4; L-iditol 2-dehydrogenase; EC 1.1.1.14; Polyol dehydrogenase; Ribitol dehydrogenase; RDH; EC 1.1.1.56; Xylitol dehydrogenase; XDH; EC 1.1.1.9
• Gene Name: SORD
• Related Disease:
  Charcot marie tooth disease
  Neuronopathy, distal hereditary motor, autosomal recessive 8
• UniProt ID: DHSO_HUMAN
• PDB ID: 1PL6; 1PL7; 1PL8
• EC Number: 1.1.1.-; 1.1.1.14; 1.1.1.4; 1.1.1.56; 1.1.1.9
• Pfam ID: PF08240 ; PF00107
• Sequence:
  MAAAAKPNNLSLVVHGPGDLRLENYPIPEPGPNEVLLRMHSVGICGSDVHYWEYGRIGNF
  IVKKPMVLGHEASGTVEKVGSSVKHLKPGDRVAIEPGAPRENDEFCKMGRYNLSPSIFFC
  ATPPDDGNLCRFYKHNAAFCYKLPDNVTFEEGALIEPLSVGIHACRRGGVTLGHKVLVCG
  AGPIGMVTLLVAKAMGAAQVVVTDLSATRLSKAKEIGADLVLQISKESPQEIARKVEGQL
  GCKPEVTIECTGAEASIQAGIYATRSGGNLVLVGLGSEMTTVPLLHAAIREVDIKGVFRY
  CNTWPVAISMLASKSVNVKPLVTHRFPLEKALEAFETFKKGLGLKIMLKCDPSDQNP
• Function: Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols. Is mostly active with D-sorbitol (D-glucitol), L-threitol, xylitol and ribitol as substrates, leading to the C2-oxidized products D-fructose, L-erythrulose, D-xylulose, and D-ribulose, respectively. Is a key enzyme in the polyol pathway that interconverts glucose and fructose via sorbitol, which constitutes an important alternate route for glucose metabolism. The polyol pathway is believed to be involved in the etiology of diabetic complications, such as diabetic neuropathy and retinopathy, induced by hyperglycemia. May play a role in sperm motility by using sorbitol as an alternative energy source for sperm motility. May have a more general function in the metabolism of secondary alcohols since it also catalyzes the stereospecific oxidation of (2R,3R)-2,3-butanediol. To a lesser extent, can also oxidize L-arabinitol, galactitol and D-mannitol and glycerol in vitro. Oxidizes neither ethanol nor other primary alcohols. Cannot use NADP(+) as the electron acceptor.
• Tissue Specificity: Expressed in liver . Expressed in kidney and epithelial cells of both benign and malignant prostate tissue. Expressed in epididymis (at protein level).
• KEGG Pathway:
  Pentose and glucuro.te interconversions (hsa00040)
  Fructose and mannose metabolism (hsa00051)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Formation of xylulose-5-phosphate (R-HSA-5661270)
  Fructose biosynthesis (R-HSA-5652227)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot marie tooth disease	DIS3BT2L	Definitive	Autosomal recessive	[1]
Neuronopathy, distal hereditary motor, autosomal recessive 8	DISI2OS3	Strong	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sorbitol	DMAN0DE	Approved	Sorbitol dehydrogenase (SORD) increases the abundance of Sorbitol.	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Halothane	DM80OZ5	Approved	Sorbitol dehydrogenase (SORD) increases the Hepatotoxicity ADR of Halothane.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Sorbitol dehydrogenase (SORD).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sorbitol dehydrogenase (SORD).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sorbitol dehydrogenase (SORD).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sorbitol dehydrogenase (SORD).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sorbitol dehydrogenase (SORD).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Sorbitol dehydrogenase (SORD).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Sorbitol dehydrogenase (SORD).	[9]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Sorbitol dehydrogenase (SORD).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Sorbitol dehydrogenase (SORD).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Sorbitol dehydrogenase (SORD).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Sorbitol dehydrogenase (SORD).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sorbitol dehydrogenase (SORD).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sorbitol dehydrogenase (SORD).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sorbitol dehydrogenase (SORD).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sorbitol dehydrogenase (SORD).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sorbitol dehydrogenase (SORD).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sorbitol dehydrogenase (SORD).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sorbitol dehydrogenase (SORD).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Sorbitol dehydrogenase (SORD).	[20]
Uric acid	DMA1MKT	Investigative	Uric acid increases the expression of Sorbitol dehydrogenase (SORD).	[21]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nat Genet. 2020 May;52(5):473-481. doi: 10.1038/s41588-020-0615-4. Epub 2020 May 4.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] 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.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Casodex treatment induces hypoxia-related gene expression in the LNCaP prostate cancer progression model. BMC Urol. 2005 Mar 24;5:5.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
• [13] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [14] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [21] Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats. J Biol Chem. 2019 Mar 15;294(11):4272-4281. doi: 10.1074/jbc.RA118.006158. Epub 2019 Jan 16.
• [22] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.