Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO7FJA9)

• DOT Name: 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1)
• Synonyms: 11-DH; 11-beta-HSD1; EC 1.1.1.146; 7-oxosteroid reductase; EC 1.1.1.201; Corticosteroid 11-beta-dehydrogenase isozyme 1; Short chain dehydrogenase/reductase family 26C member 1
• Gene Name: HSD11B1
• Related Disease:
  Cortisone reductase deficiency
  Cortisone reductase deficiency 2
• UniProt ID: DHI1_HUMAN
• PDB ID: 1XU7 ; 1XU9 ; 2BEL ; 2ILT ; 2IRW ; 2RBE ; 3BYZ ; 3BZU ; 3CH6 ; 3CZR ; 3D3E ; 3D4N ; 3D5Q ; 3EY4 ; 3FCO ; 3FRJ ; 3H6K ; 3HFG ; 3OQ1 ; 3PDJ ; 3QQP ; 3TFQ ; 4BB5 ; 4BB6 ; 4C7J ; 4C7K ; 4HFR ; 4HX5 ; 4IJU ; 4IJV ; 4IJW ; 4K1L ; 4P38 ; 4YYZ ; 5PGU ; 5PGV ; 5PGW ; 5PGX ; 5PGY ; 5QII
• EC Number: 1.1.1.146; 1.1.1.201
• Pfam ID: PF00106
• Sequence:
  MAFMKKYLLPILGLFMAYYYYSANEEFRPEMLQGKKVIVTGASKGIGREMAYHLAKMGAH
  VVVTARSKETLQKVVSHCLELGAASAHYIAGTMEDMTFAEQFVAQAGKLMGGLDMLILNH
  ITNTSLNLFHDDIHHVRKSMEVNFLSYVVLTVAALPMLKQSNGSIVVVSSLAGKVAYPMV
  AAYSASKFALDGFFSSIRKEYSVSRVNVSITLCVLGLIDTETAMKAVSGIVHMQAAPKEE
  CALEIIKGGALRQEEVYYDSSLWTTLLIRNPCRKILEFLYSTSYNMDRFINK
• Function: Controls the reversible conversion of biologically active glucocorticoids such as cortisone to cortisol, and 11-dehydrocorticosterone to corticosterone in the presence of NADP(H). Participates in the corticosteroid receptor-mediated anti-inflammatory response, as well as metabolic and homeostatic processes. Plays a role in the secretion of aqueous humor in the eye, maintaining a normotensive, intraocular environment. Bidirectional in vitro, predominantly functions as a reductase in vivo, thereby increasing the concentration of active glucocorticoids. It has broad substrate specificity, besides glucocorticoids, it accepts other steroid and sterol substrates. Interconverts 7-oxo- and 7-hydroxy-neurosteroids such as 7-oxopregnenolone and 7beta-hydroxypregnenolone, 7-oxodehydroepiandrosterone (3beta-hydroxy-5-androstene-7,17-dione) and 7beta-hydroxydehydroepiandrosterone (3beta,7beta-dihydroxyandrost-5-en-17-one), among others. Catalyzes the stereo-specific conversion of the major dietary oxysterol, 7-ketocholesterol (7-oxocholesterol), into the more polar 7-beta-hydroxycholesterol metabolite. 7-oxocholesterol is one of the most important oxysterols, it participates in several events such as induction of apoptosis, accumulation in atherosclerotic lesions, lipid peroxidation, and induction of foam cell formation. Mediates the 7-oxo reduction of 7-oxolithocholate mainly to chenodeoxycholate, and to a lesser extent to ursodeoxycholate, both in its free form and when conjugated to glycine or taurine, providing a link between glucocorticoid activation and bile acid metabolism. Catalyzes the synthesis of 7-beta-25-dihydroxycholesterol from 7-oxo-25-hydroxycholesterol in vitro, which acts as a ligand for the G-protein-coupled receptor (GPCR) Epstein-Barr virus-induced gene 2 (EBI2) and may thereby regulate immune cell migration.
• Tissue Specificity: Widely expressed, highest expression in liver, lower in testis, ovary, lung, foreskin fibroblasts, and much lower in kidney . Expressed in liver (at protein level) . Expressed in the basal cells of the corneal epithelium and in the ciliary nonpigmented epithelium (both at mRNA and at protein level) .
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Metabolic pathways (hsa01100)
  Chemical carcinogenesis - D. adducts (hsa05204)
• Reactome Pathway:
  Prednisone ADME (R-HSA-9757110)
  Glucocorticoid biosynthesis (R-HSA-194002)
• BioCyc Pathway: MetaCyc:HS04154-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cortisone reductase deficiency	DIS88XDM	Supportive	Autosomal dominant	[1]
Cortisone reductase deficiency 2	DISSA1XS	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cortisone	DMU5QZX	Approved	11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1) increases the metabolism of Cortisone.	[25]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
BRN-3548355	DM4KXT0	Investigative	11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1) increases the reduction of BRN-3548355.	[26]

30 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 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol affects the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[8]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[8]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine affects the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[15]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[12]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[8]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[7]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[8]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the activity of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[16]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the activity of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[17]
Metyrapone	DMI7FVQ	Approved	Metyrapone decreases the activity of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[18]
BUTAPROST	DMVYNJZ	Patented	BUTAPROST increases the activity of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[16]
PF-915275	DMB7EIN	Discontinued in Phase 1	PF-915275 decreases the activity of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[22]
N-nonylphenol	DMH3OUX	Investigative	N-nonylphenol decreases the activity of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[23]
HPTE	DMRPZD4	Investigative	HPTE decreases the activity of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[24]

2 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 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of 11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1).	[21]

References

• [1] Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1. Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4111-6. doi: 10.1073/pnas.1014934108. Epub 2011 Feb 15.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Role of calcitriol and cortisol on human adipocyte proliferation and oxidative and inflammatory stress: a microarray study. J Nutrigenet Nutrigenomics. 2008;1(1-2):30-48. doi: 10.1159/000109873. Epub 2007 Oct 16.
• [7] Testosterone stimulates adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in a depot-specific manner in children. J Clin Endocrinol Metab. 2010 Jul;95(7):3300-8.
• [8] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [11] Dexamethasone and the inflammatory response in explants of human omental adipose tissue. Mol Cell Endocrinol. 2010 Feb 5;315(1-2):292-8.
• [12] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [13] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [14] Effects of chronic rosiglitazone therapy on gene expression in human adipose tissue in vivo in patients with type 2 diabetes. J Clin Endocrinol Metab. 2007 Feb;92(2):720-4.
• [15] Adipocyte differentiation, mitochondrial gene expression and fat distribution: differences between zidovudine and tenofovir after 6 months. Antivir Ther. 2009;14(8):1089-100. doi: 10.3851/IMP1457.
• [16] PTGER1 and PTGER2 receptors mediate regulation of progesterone synthesis and type 1 11beta-hydroxysteroid dehydrogenase activity by prostaglandin E2 in human granulosa lutein cells. J Endocrinol. 2007 Sep;194(3):595-602.
• [17] In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I. Eur J Endocrinol. 2000 Feb;142(2):200-7.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] 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.
• [20] Induction of 11-HSD 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells. Mol Endocrinol. 2013 Feb;27(2):192-202. doi: 10.1210/me.2012-1247. Epub 2012 Dec 28.
• [21] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Inhibitory effects of some possible endocrine-disrupting chemicals on the isozymes of human 11beta-hydroxysteroid dehydrogenase and expression of their mRNA in gonads and adrenal glands. Environ Sci. 2005;12(4):219-30.
• [24] Effects of methoxychlor and its metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane on 11beta-hydroxysteroid dehydrogenase activities in vitro. Toxicol Lett. 2013 Mar 27;218(1):18-23.
• [25] Local amplification of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes. J Immunol. 2006 Jun 15;176(12):7605-11. doi: 10.4049/jimmunol.176.12.7605.
• [26] Sex hormones reduce NNK detoxification through inhibition of short-chain dehydrogenases/reductases and aldo-keto reductases in?vitro. Chem Biol Interact. 2017 Oct 1;276:167-173. doi: 10.1016/j.cbi.2017.02.016. Epub 2017 Feb 28.