Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4217NK)

• DOT Name: High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B)
• Synonyms: HsPDE8B; EC 3.1.4.53; Cell proliferation-inducing gene 22 protein
• Gene Name: PDE8B
• Related Disease:
  Adenoma
  Adrenal adenoma
  Adrenal gland neoplasm
  Alzheimer disease
  Autoimmune disease
  Autosomal dominant striatal neurodegeneration type 1
  Carney-Stratakis syndrome
  Gastrointestinal stromal tumour
  Hyperthyroidism
  Hypothyroidism
  Movement disorder
  Multiple endocrine neoplasia
  Multiple endocrine neoplasia type 1
  Myocardial infarction
  Neoplasm
  Paraganglioma
  Parkinson disease
  Parkinsonian disorder
  Pheochromocytoma
  Pigmented nodular adrenocortical disease, primary, 3
  Congenital adrenal hyperplasia
  Primary pigmented nodular adrenocortical disease
  Striatal degeneration, autosomal dominant
  Acute myelogenous leukaemia
  Schizophrenia
• UniProt ID: PDE8B_HUMAN
• EC Number: 3.1.4.53
• Pfam ID: PF13426 ; PF08629 ; PF00233
• Sequence:
  MGCAPSIHVSQSGVIYCRDSDESSSPRQTTSVSQGPAAPLPGLFVQTDAADAIPPSRASG
  PPSVARVRRARTELGSGSSAGSAAPAATTSRGRRRHCCSSAEAETQTCYTSVKQVSSAEV
  RIGPMRLTQDPIQVLLIFAKEDSQSDGFWWACDRAGYRCNIARTPESALECFLDKHHEII
  VIDHRQTQNFDAEAVCRSIRATNPSEHTVILAVVSRVSDDHEEASVLPLLHAGFNRRFME
  NSSIIACYNELIQIEHGEVRSQFKLRACNSVFTALDHCHEAIEITSDDHVIQYVNPAFER
  MMGYHKGELLGKELADLPKSDKNRADLLDTINTCIKKGKEWQGVYYARRKSGDSIQQHVK
  ITPVIGQGGKIRHFVSLKKLCCTTDNNKQIHKIHRDSGDNSQTEPHSFRYKNRRKESIDV
  KSISSRGSDAPSLQNRRYPSMARIHSMTIEAPITKVINIINAAQENSPVTVAEALDRVLE
  ILRTTELYSPQLGTKDEDPHTSDLVGGLMTDGLRRLSGNEYVFTKNVHQSHSHLAMPITI
  NDVPPCISQLLDNEESWDFNIFELEAITHKRPLVYLGLKVFSRFGVCEFLNCSETTLRAW
  FQVIEANYHSSNAYHNSTHAADVLHATAFFLGKERVKGSLDQLDEVAALIAATVHDVDHP
  GRTNSFLCNAGSELAVLYNDTAVLESHHTALAFQLTVKDTKCNIFKNIDRNHYRTLRQAI
  IDMVLATEMTKHFEHVNKFVNSINKPMAAEIEGSDCECNPAGKNFPENQILIKRMMIKCA
  DVANPCRPLDLCIEWAGRISEEYFAQTDEEKRQGLPVVMPVFDRNTCSIPKSQISFIDYF
  ITDMFDAWDAFAHLPALMQHLADNYKHWKTLDDLKCKSLRLPSDS
• Function: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in specific signaling in the thyroid gland.
• Tissue Specificity: Abundantly expressed in the thyroid. Also very weakly expressed in brain, spinal cord and placenta. In the thyroid isoform 1 predominates, and isoforms 2 and 6 are also highly expressed. In the placenta isoforms 1 and 2 are expressed equally. In the brain isoform 2 predominates.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
  Morphine addiction (hsa05032)
• Reactome Pathway: G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Biomarker	[1]
Adrenal adenoma	DISC2UN8	Strong	Genetic Variation	[2]
Adrenal gland neoplasm	DISFK7RF	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[5]
Autosomal dominant striatal neurodegeneration type 1	DISSCDO4	Strong	Autosomal dominant	[6]
Carney-Stratakis syndrome	DISP3P3F	Strong	Genetic Variation	[2]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Genetic Variation	[2]
Hyperthyroidism	DISX87ZH	Strong	Genetic Variation	[7]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[8]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[9]
Multiple endocrine neoplasia	DISZGBKW	Strong	Genetic Variation	[2]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Genetic Variation	[2]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[2]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[9]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[9]
Pheochromocytoma	DIS56IFV	Strong	Genetic Variation	[2]
Pigmented nodular adrenocortical disease, primary, 3	DISGN56J	Strong	Autosomal dominant	[12]
Congenital adrenal hyperplasia	DISG873W	moderate	Genetic Variation	[13]
Primary pigmented nodular adrenocortical disease	DISXCNDR	Supportive	Autosomal dominant	[11]
Striatal degeneration, autosomal dominant	DISTLABZ	Supportive	Autosomal dominant	[14]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[15]
Schizophrenia	DISSRV2N	No Known	Unknown	[16]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B) increases the hydrolysis of [3H]cAMP.	[25]

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 High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[20]
Roflumilast	DMPGHY8	Approved	Roflumilast decreases the activity of High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[21]
Trequinsin	DMQRSMD	Terminated	Trequinsin decreases the activity of High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B).	[24]

References

• [1] Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs(alpha) mutations.J Clin Endocrinol Metab. 2001 Aug;86(8):3795-800. doi: 10.1210/jcem.86.8.7779.
• [2] Multiple endocrine neoplasias: advances and challenges for the future.J Intern Med. 2009 Jul;266(1):1-4. doi: 10.1111/j.1365-2796.2009.02108.x.
• [3] Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP-specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumours.Clin Endocrinol (Oxf). 2012 Aug;77(2):195-9. doi: 10.1111/j.1365-2265.2012.04366.x.
• [4] Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer's disease brains examined by in situ hybridization.Exp Neurol. 2003 Aug;182(2):322-34. doi: 10.1016/s0014-4886(03)00042-6.
• [5] Novel associations for hypothyroidism include known autoimmune risk loci.PLoS One. 2012;7(4):e34442. doi: 10.1371/journal.pone.0034442. Epub 2012 Apr 6.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.Nat Commun. 2018 Oct 26;9(1):4455. doi: 10.1038/s41467-018-06356-1.
• [8] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [9] Clinical findings of autosomal-dominant striatal degeneration and PDE8B mutation screening in parkinsonism and related disorders.Parkinsonism Relat Disord. 2019 Dec;69:94-98. doi: 10.1016/j.parkreldis.2019.11.002. Epub 2019 Nov 5.
• [10] The phosphodiesterase 8B gene rs4704397 is associated with thyroid function, risk of myocardial infarction, and body height: the Troms study.Thyroid. 2014 Feb;24(2):215-22. doi: 10.1089/thy.2013.0177. Epub 2013 Nov 13.
• [11] A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. Eur J Hum Genet. 2008 Oct;16(10):1245-53. doi: 10.1038/ejhg.2008.85. Epub 2008 Apr 23.
• [12] Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. N Engl J Med. 2008 Feb 14;358(7):750-2. doi: 10.1056/NEJMc0706182.
• [13] Carney complex and other conditions associated with micronodular adrenal hyperplasias.Best Pract Res Clin Endocrinol Metab. 2010 Dec;24(6):907-14. doi: 10.1016/j.beem.2010.10.006.
• [14] Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene. Am J Hum Genet. 2010 Jan;86(1):83-7. doi: 10.1016/j.ajhg.2009.12.003.
• [15] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [16] Double hits in schizophrenia. Hum Mol Genet. 2018 Aug 1;27(15):2755-2761. doi: 10.1093/hmg/ddy175.
• [17] 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.
• [18] 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.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [21] Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors. J Pharmacol Exp Ther. 2005 Aug;314(2):846-54. doi: 10.1124/jpet.105.083519. Epub 2005 May 18.
• [22] 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.
• [23] 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.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [25] Molecular cloning and characterization of human PDE8B, a novel thyroid-specific isozyme of 3',5'-cyclic nucleotide phosphodiesterase. Biochem Biophys Res Commun. 1998 Sep 29;250(3):751-6. doi: 10.1006/bbrc.1998.9379.