Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5GBOVJ)

• DOT Name: Lutropin subunit beta (LHB)
• Synonyms: Lutropin beta chain; Luteinizing hormone subunit beta; LH-B; LSH-B; LSH-beta
• Gene Name: LHB
• Related Disease:
  Hypogonadism
  Alcohol dependence
  Alcohol use disorder
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Central precocious puberty
  Endometriosis
  High blood pressure
  Hyperthyroidism
  Hypogonadism, male
  Hypogonadotropic hypogonadism 23 with or without anosmia
  Lipodystrophy
  Male infertility
  Overnutrition
  Polycystic ovarian syndrome
  Precocious puberty
  Prostate neoplasm
  Female hypogonadism
  Female infertility
  Hyperprolactinaemia
  Hepatocellular carcinoma
• UniProt ID: LSHB_HUMAN
• Pfam ID: PF00007
• Sequence:
  MEMLQGLLLLLLLSMGGAWASREPLRPWCHPINAILAVEKEGCPVCITVNTTICAGYCPT
  MMRVLQAVLPPLPQVVCTYRDVRFESIRLPGCPRGVDPVVSFPVALSCRCGPCRRSTSDC
  GGPKDHPLTCDHPQLSGLLFL
• Function: Promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids.
• Tissue Specificity: Pituitary gland.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  GnRH sig.ling pathway (hsa04912)
  Ovarian steroidogenesis (hsa04913)
  Prolactin sig.ling pathway (hsa04917)
  GnRH secretion (hsa04929)
• Reactome Pathway:
  Mineralocorticoid biosynthesis (R-HSA-193993)
  Glycoprotein hormones (R-HSA-209822)
  Hormone ligand-binding receptors (R-HSA-375281)
  G alpha (s) signalling events (R-HSA-418555)
  Reactions specific to the complex N-glycan synthesis pathway (R-HSA-975578)
  Androgen biosynthesis (R-HSA-193048)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadism	DISICMNI	Definitive	Genetic Variation	[1]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[2]
Alcohol use disorder	DISMB65Y	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Central precocious puberty	DISW1TFK	Strong	Biomarker	[4]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	Strong	Biomarker	[6]
Hyperthyroidism	DISX87ZH	Strong	Altered Expression	[7]
Hypogonadism, male	DISV1F5R	Strong	Genetic Variation	[1]
Hypogonadotropic hypogonadism 23 with or without anosmia	DISYNM6Y	Strong	Autosomal recessive	[8]
Lipodystrophy	DIS3SGVD	Strong	Altered Expression	[9]
Male infertility	DISY3YZZ	Strong	Biomarker	[10]
Overnutrition	DISGAJIG	Strong	Altered Expression	[11]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[12]
Precocious puberty	DISYI2XZ	Strong	Biomarker	[4]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[13]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[14]
Female infertility	DIS9GNYZ	moderate	Biomarker	[15]
Hyperprolactinaemia	DISLIZS4	moderate	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Limited	Genetic Variation	[17]

This DOT Affected the Regulation of Drug Effects of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Lutropin subunit beta (LHB) increases the abundance of Testosterone.	[39]
Progesterone	DMUY35B	Approved	Lutropin subunit beta (LHB) decreases the abundance of Progesterone.	[39]
[3H]cAMP	DMZRQU7	Investigative	Lutropin subunit beta (LHB) increases the abundance of [3H]cAMP.	[40]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	Lutropin subunit beta (LHB) increases the abundance of 4-ANDROSTENE-3-17-DIONE.	[39]

2 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 Lutropin subunit beta (LHB).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Lutropin subunit beta (LHB).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lutropin subunit beta (LHB).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the activity of Lutropin subunit beta (LHB).	[20]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the activity of Lutropin subunit beta (LHB).	[20]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of Lutropin subunit beta (LHB).	[23]
Cetrorelix	DMFD9Q6	Approved	Cetrorelix decreases the expression of Lutropin subunit beta (LHB).	[25]
Letrozole	DMH07Y3	Approved	Letrozole increases the expression of Lutropin subunit beta (LHB).	[26]
Bromocriptine	DMVE3TK	Approved	Bromocriptine increases the expression of Lutropin subunit beta (LHB).	[27]
Cenestin	DMXQS7K	Approved	Cenestin decreases the expression of Lutropin subunit beta (LHB).	[28]
Naloxone	DM3FXMA	Approved	Naloxone increases the expression of Lutropin subunit beta (LHB).	[30]
Metoclopramide	DMFA5MY	Approved	Metoclopramide increases the expression of Lutropin subunit beta (LHB).	[30]
Naltrexone	DMUL45H	Approved	Naltrexone increases the expression of Lutropin subunit beta (LHB).	[31]
Oestradiol valerate and dienogest	DMZK0FQ	Approved	Oestradiol valerate and dienogest decreases the expression of Lutropin subunit beta (LHB).	[32]
Leuprorelin acetate	DM15HAT	Approved	Leuprorelin acetate decreases the expression of Lutropin subunit beta (LHB).	[33]
Ganirelix	DMGMB30	Approved	Ganirelix decreases the expression of Lutropin subunit beta (LHB).	[35]
Cyproterone acetate	DMLMOIJ	Phase 4	Cyproterone acetate decreases the expression of Lutropin subunit beta (LHB).	[32]
Avosentan	DM2I8NT	Discontinued in Phase 2	Avosentan increases the expression of Lutropin subunit beta (LHB).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the activity of Lutropin subunit beta (LHB).	[20]
Hydroxyestrone	DMBO7ZD	Investigative	Hydroxyestrone decreases the expression of Lutropin subunit beta (LHB).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the secretion of Lutropin subunit beta (LHB).	[21]
Nicotine	DMWX5CO	Approved	Nicotine increases the secretion of Lutropin subunit beta (LHB).	[22]
Cocaine	DMSOX7I	Approved	Cocaine increases the secretion of Lutropin subunit beta (LHB).	[22]
Crizotinib	DM4F29C	Approved	Crizotinib decreases the secretion of Lutropin subunit beta (LHB).	[24]
Levonorgestrel	DM1DP7T	Approved	Levonorgestrel decreases the secretion of Lutropin subunit beta (LHB).	[29]
Alprazolam	DMC7XDN	Approved	Alprazolam increases the secretion of Lutropin subunit beta (LHB).	[34]
Norethindrone acetate	DMDGCQP	Approved	Norethindrone acetate decreases the secretion of Lutropin subunit beta (LHB).	[29]

References

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• [4] Update on the etiology, diagnosis and therapeutic management of sexual precocity.Arq Bras Endocrinol Metabol. 2008 Feb;52(1):18-31. doi: 10.1590/s0004-27302008000100005.
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• [8] Targeted disruption of luteinizing hormone beta-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17294-9. doi: 10.1073/pnas.0404743101. Epub 2004 Nov 29.
• [9] Leptin restores markers of female fertility in lipodystrophy.Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3292-3297. doi: 10.1016/j.bbadis.2018.07.015. Epub 2018 Jul 23.
• [10] Hypogonadism in a patient with a mutation in the luteinizing hormone beta-subunit gene.N Engl J Med. 2004 Dec 16;351(25):2619-25. doi: 10.1056/NEJMoa040326.
• [11] Neonatal Overnutrition Increases Testicular Size and Expression of Luteinizing Hormone -Subunit in Peripubertal Male Rats.Front Endocrinol (Lausanne). 2018 Apr 13;9:168. doi: 10.3389/fendo.2018.00168. eCollection 2018.
• [12] Association between genes encoding components of the Leutinizing hormone/Luteinizing hormone-choriogonadotrophin receptor pathway and polycystic ovary syndrome in Egyptian women.IUBMB Life. 2016 Jan;68(1):23-36. doi: 10.1002/iub.1457. Epub 2015 Dec 14.
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• [14] Increased prevalence of luteinizing hormone beta-subunit variant in patients with premature ovarian failure.Fertil Steril. 1999 Jan;71(1):96-101. doi: 10.1016/s0015-0282(98)00409-9.
• [15] A new molecular variant of luteinizing hormone associated with female infertility.Fertil Steril. 1998 Jan;69(1):102-6. doi: 10.1016/s0015-0282(97)00445-7.
• [16] Pituitary sensitivity to LHRH in hyperprolactinemia induced by perphenazine and renal pituitary transplants in female rats.Biol Reprod. 1980 Apr;22(3):486-92. doi: 10.1095/biolreprod22.3.486.
• [17] A nonsense mutant of the hepatitis B virus large S protein antagonizes multiple tumor suppressor pathways through c-Jun activation domain-binding protein1.PLoS One. 2019 Mar 14;14(3):e0208665. doi: 10.1371/journal.pone.0208665. eCollection 2019.
• [18] 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.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Estrogenic Compounds or Adiponectin Inhibit Cyclic AMP Response to Human Luteinizing Hormone in Mouse Leydig Tumor Cells. Biology (Basel). 2019 Jun 11;8(2):45. doi: 10.3390/biology8020045.
• [21] Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard. Arch Toxicol. 2021 Feb;95(2):727-747. doi: 10.1007/s00204-020-02946-5. Epub 2021 Jan 25.
• [22] Effects of intravenous cocaine and cigarette smoking on luteinizing hormone, testosterone, and prolactin in men. J Pharmacol Exp Ther. 2003 Oct;307(1):339-48. doi: 10.1124/jpet.103.052928. Epub 2003 Jul 31.
• [23] Exploration for drug therapy in endometrial carcinoma. Chin Med J (Engl). 1996 May;109(5):356-60.
• [24] 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.
• [25] 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.
• [26] Aromatase inhibition, testosterone, and seizures. Epilepsy Behav. 2004 Apr;5(2):260-3. doi: 10.1016/j.yebeh.2003.12.001.
• [27] Resolution of hyperprolactinaemia after bromocriptine-induced pregnancy. Lancet. 1979 Apr 7;1(8119):784-5. doi: 10.1016/s0140-6736(79)91247-9.
• [28] 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.
• [29] Relative progestational and androgenic activity of four progestins used for male hormonal contraception assessed in vitro in relation to their ability to suppress LH secretion in the castrate male rat. Mol Cell Endocrinol. 2010 Oct 26;328(1-2):16-21. doi: 10.1016/j.mce.2010.06.010. Epub 2010 Jun 25.
• [30] Differences in the opioid control of luteinizing hormone secretion between pathological and iatrogenic hyperprolactinemic states. J Clin Endocrinol Metab. 1987 Mar;64(3):508-12. doi: 10.1210/jcem-64-3-508.
• [31] 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.
• [32] 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.
• [33] Erectile function and nocturnal penile tumescence in patients with prostate cancer undergoing luteinizing hormone-releasing hormone agonist therapy. Int J Urol. 1999 Jan;6(1):19-23. doi: 10.1046/j.1442-2042.1999.06128.x.
• [34] The effect of alprazolam on serum cortisol and luteinizing hormone pulsatility in normal women and in women with stress-related anovulation. J Clin Endocrinol Metab. 1995 Mar;80(3):818-23. doi: 10.1210/jcem.80.3.7883836.
• [35] Progesterone rise on HCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression. Reprod Biomed Online. 2011 Mar;22(3):263-71. doi: 10.1016/j.rbmo.2010.11.002. Epub 2010 Nov 13.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] Analysis of androgen receptor and anti-Mllerian hormone pathways in human granulosa cells under luteinizing hormone treatment. Reprod Biol Endocrinol. 2013 Feb 21;11:11. doi: 10.1186/1477-7827-11-11.
• [40] In vitro effects of the endocrine disruptor p,p'DDT on human choriogonadotropin/luteinizing hormone receptor signalling. Arch Toxicol. 2021 May;95(5):1671-1681. doi: 10.1007/s00204-021-03007-1. Epub 2021 Feb 27.