Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGLS283)

• DOT Name: Follitropin subunit beta (FSHB)
• Synonyms: Follicle-stimulating hormone beta subunit; FSH-B; FSH-beta; Follitropin beta chain
• Gene Name: FSHB
• Related Disease: Hypogonadotropic hypogonadism 24 without anosmia
• UniProt ID: FSHB_HUMAN
• PDB ID: 1FL7; 1XWD; 4AY9; 4MQW; 8I2G
• Pfam ID: PF00007
• Sequence:
  MKTLQFFFLFCCWKAICCNSCELTNITIAIEKEECRFCISINTTWCAGYCYTRDLVYKDP
  ARPKIQKTCTFKELVYETVRVPGCAHHADSLYTYPVATQCHCGKCDSDSTDCTVRGLGPS
  YCSFGEMKE
• Function: Together with the alpha chain CGA constitutes follitropin, the follicle-stimulating hormone, and provides its biological specificity to the hormone heterodimer. Binds FSHR, a G protein-coupled receptor, on target cells to activate downstream signaling pathways. Follitropin is involved in follicle development and spermatogenesis in reproductive organs.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  GnRH sig.ling pathway (hsa04912)
  Ovarian steroidogenesis (hsa04913)
• Reactome Pathway:
  Hormone ligand-binding receptors (R-HSA-375281)
  G alpha (s) signalling events (R-HSA-418555)
  Glycoprotein hormones (R-HSA-209822)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadotropic hypogonadism 24 without anosmia	DISP08RC	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Follitropin subunit beta (FSHB) increases the secretion of Testosterone.	[20]
Progesterone	DMUY35B	Approved	Follitropin subunit beta (FSHB) increases the abundance of Progesterone.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Follitropin subunit beta (FSHB).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Follitropin subunit beta (FSHB).	[3]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Follitropin subunit beta (FSHB).	[4]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Follitropin subunit beta (FSHB).	[3]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Follitropin subunit beta (FSHB).	[5]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of Follitropin subunit beta (FSHB).	[6]
Cimetidine	DMH61ZB	Approved	Cimetidine affects the expression of Follitropin subunit beta (FSHB).	[8]
Cetrorelix	DMFD9Q6	Approved	Cetrorelix decreases the expression of Follitropin subunit beta (FSHB).	[9]
Letrozole	DMH07Y3	Approved	Letrozole increases the expression of Follitropin subunit beta (FSHB).	[10]
Risperidone	DMN6DXL	Approved	Risperidone affects the expression of Follitropin subunit beta (FSHB).	[11]
Bromocriptine	DMVE3TK	Approved	Bromocriptine increases the expression of Follitropin subunit beta (FSHB).	[12]
Cenestin	DMXQS7K	Approved	Cenestin decreases the expression of Follitropin subunit beta (FSHB).	[3]
Naltrexone	DMUL45H	Approved	Naltrexone increases the expression of Follitropin subunit beta (FSHB).	[13]
Oestradiol valerate and dienogest	DMZK0FQ	Approved	Oestradiol valerate and dienogest decreases the expression of Follitropin subunit beta (FSHB).	[14]
Goserelin	DMAT8CG	Approved	Goserelin decreases the expression of Follitropin subunit beta (FSHB).	[15]
Cyproterone acetate	DMLMOIJ	Phase 4	Cyproterone acetate decreases the expression of Follitropin subunit beta (FSHB).	[14]
Triciribine	DM8IC5H	Phase 1/2	Triciribine decreases the activity of Follitropin subunit beta (FSHB).	[16]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the activity of Follitropin subunit beta (FSHB).	[16]
Avosentan	DM2I8NT	Discontinued in Phase 2	Avosentan increases the expression of Follitropin subunit beta (FSHB).	[18]
Hydroxyestrone	DMBO7ZD	Investigative	Hydroxyestrone decreases the expression of Follitropin subunit beta (FSHB).	[19]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Crizotinib	DM4F29C	Approved	Crizotinib decreases the secretion of Follitropin subunit beta (FSHB).	[7]

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 increases the methylation of Follitropin subunit beta (FSHB).	[17]

References

• [1] FSH beta gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. J Clin Endocrinol Metab. 2002 Aug;87(8):3702-7. doi: 10.1210/jcem.87.8.8724.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Estrogens exert route- and dose-dependent effects on insulin-like growth factor (IGF)-binding protein-3 and the acid-labile subunit of the IGF ternary complex. J Clin Endocrinol Metab. 2000 May;85(5):1918-22. doi: 10.1210/jcem.85.5.6527.
• [4] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [5] Suppression of spermatogenesis in patients with Beh?et's disease treated with cyclophosphamide and colchicine. Fertil Steril. 1981 Jul;36(1):76-80. doi: 10.1016/s0015-0282(16)45622-0.
• [6] Exploration for drug therapy in endometrial carcinoma. Chin Med J (Engl). 1996 May;109(5):356-60.
• [7] Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer. 2012 Nov 1;118(21):5302-9. doi: 10.1002/cncr.27450. Epub 2012 Apr 4.
• [8] Male sexual dysfunction during treatment with cimetidine. Br Med J. 1979 Mar 10;1(6164):659. doi: 10.1136/bmj.1.6164.659.
• [9] Pharmacokinetics of new testosterone transdermal therapeutic systems in gonadotropin-releasing hormone antagonist-suppressed normal men. Exp Clin Endocrinol Diabetes. 1999;107(1):63-9. doi: 10.1055/s-0029-1212075.
• [10] Aromatase inhibition, testosterone, and seizures. Epilepsy Behav. 2004 Apr;5(2):260-3. doi: 10.1016/j.yebeh.2003.12.001.
• [11] Effect of risperidone and olanzapine on reproductive hormones, psychopathology and sexual functioning in male patients with schizophrenia. Psychoneuroendocrinology. 2009 Jan;34(1):129-39. doi: 10.1016/j.psyneuen.2008.08.015. Epub 2008 Oct 5.
• [12] Resolution of hyperprolactinaemia after bromocriptine-induced pregnancy. Lancet. 1979 Apr 7;1(8119):784-5. doi: 10.1016/s0140-6736(79)91247-9.
• [13] Chronic naltrexone treatment induces desensitization of the luteinizing hormone pulse generator for opioid blockade in hyperprolactinemic patients. J Clin Endocrinol Metab. 1995 May;80(5):1739-42. doi: 10.1210/jcem.80.5.7745028.
• [14] Twenty-one day administration of dienogest reversibly suppresses gonadotropins and testosterone in normal men. J Clin Endocrinol Metab. 2002 May;87(5):2107-13. doi: 10.1210/jcem.87.5.8514.
• [15] [Kuntai capsule combined with gonadotropin releasing hormone agonist in treatment of moderate-severe endometriosis: a clinical observation]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014 Nov;34(11):1288-91.
• [16] Inhibitory roles of prohibitin and chemerin in FSH-induced rat granulosa cell steroidogenesis. Endocrinology. 2013 Feb;154(2):956-67. doi: 10.1210/en.2012-1836. Epub 2012 Dec 18.
• [17] 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.
• [18] Influence of avosentan (SPP3OI) on the pharmacokinetics of a second generation oral contraceptive containing ethinylestradiol and levonorgestrel in healthy female volunteers. Int J Clin Pharmacol Ther. 2006 Dec;44(12):668-74. doi: 10.5414/cpp44668.
• [19] Absence of a suppressive effect of 2-hydroxyestrone on hyperprolactinemia in patients with prolactinomas before and after estradiol administration. J Clin Endocrinol Metab. 1983 Feb;56(2):230-3. doi: 10.1210/jcem-56-2-230.
• [20] In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles. Toxicol Appl Pharmacol. 2005 Apr 1;204(1):69-80. doi: 10.1016/j.taap.2004.08.009.
• [21] Gonadotrophin stimulation of non-luteinized granulosa cells increases steroid production and the expression of enzymes involved in estrogen and progesterone synthesis. Hum Reprod. 2007 Feb;22(2):401-6. doi: 10.1093/humrep/del408. Epub 2006 Nov 10.