Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW2MMOF)

• DOT Name: Aldo-keto reductase family 1 member C4 (AKR1C4)
• Synonyms: EC 1.1.1.-; EC 1.1.1.209; EC 1.1.1.210; EC 1.1.1.51; EC 1.1.1.53; EC 1.1.1.62; 3-alpha-hydroxysteroid dehydrogenase type I; 3-alpha-HSD1; EC 1.1.1.357; 3alpha-hydroxysteroid 3-dehydrogenase; Chlordecone reductase; CDR; EC 1.1.1.225; Dihydrodiol dehydrogenase 4; DD-4; DD4; HAKRA
• Gene Name: AKR1C4
• Related Disease: 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency
• UniProt ID: AK1C4_HUMAN
• PDB ID: 2FVL
• EC Number: 1.1.1.-; 1.1.1.209; 1.1.1.210; 1.1.1.225; 1.1.1.357; 1.1.1.51; 1.1.1.53; 1.1.1.62
• Pfam ID: PF00248
• Sequence:
  MDPKYQRVELNDGHFMPVLGFGTYAPPEVPRNRAVEVTKLAIEAGFRHIDSAYLYNNEEQ
  VGLAIRSKIADGSVKREDIFYTSKLWCTFFQPQMVQPALESSLKKLQLDYVDLYLLHFPM
  ALKPGETPLPKDENGKVIFDTVDLSATWEVMEKCKDAGLAKSIGVSNFNCRQLEMILNKP
  GLKYKPVCNQVECHPYLNQSKLLDFCKSKDIVLVAHSALGTQRHKLWVDPNSPVLLEDPV
  LCALAKKHKQTPALIALRYQLQRGVVVLAKSYNEQRIRENIQVFEFQLTSEDMKVLDGLN
  RNYRYVVMDFLMDHPDYPFSDEY
• Function: Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Liver specific enzyme that acts as an NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain. Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH. Acts preferentially as a 3-alpha-hydroxysteroid dehydrogenase (HSD) with a subsidiary 3-beta-HSD activity. Catalyzes efficiently the transformation of the potent androgen 5-alpha-dihydrotestosterone (5alpha-DHT or 17beta-hydroxy-5alpha-androstan-3-one) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol). Catalyzes the reduction of estrone into 17beta-estradiol but with low efficiency. Metabolizes a broad spectrum of natural and synthetic therapeutic steroid and plays an important role in metabolism of androgens, estrogens, progestereone and conjugated steroids. Catalyzes the biotransformation of the pesticide chlordecone (kepone) to its corresponding alcohol leading to increased biliary excretion of the pesticide and concomitant reduction of its neurotoxicity since bile is the major excretory route.
• Tissue Specificity: Liver specific.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway:
  Synthesis of bile acids and bile salts via 24-hydroxycholesterol (R-HSA-193775)
  Synthesis of bile acids and bile salts via 27-hydroxycholesterol (R-HSA-193807)
  Retinoid metabolism and transport (R-HSA-975634)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)
• BioCyc Pathway: MetaCyc:HS10739-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY disorder of sex development due to testicular 17,20-desmolase deficiency	DISEZQMU	Limited	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Aldo-keto reductase family 1 member C4 (AKR1C4) decreases the abundance of Progesterone.	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Aldo-keto reductase family 1 member C4 (AKR1C4) increases the metabolism of Dihydrotestosterone.	[17]
ELTANOLONE	DM38CIV	Discontinued in Phase 3	Aldo-keto reductase family 1 member C4 (AKR1C4) affects the metabolism of ELTANOLONE.	[5]

This DOT Affected the Biotransformations of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Oxcarbazepine	DM5PU6O	Approved	Aldo-keto reductase family 1 member C4 (AKR1C4) increases the reduction of Oxcarbazepine.	[16]
Phenanthrene-9,10-dione	DMG8KS9	Investigative	Aldo-keto reductase family 1 member C4 (AKR1C4) increases the reduction of Phenanthrene-9,10-dione.	[18]
tetrahydrodeoxycorticosterone	DMF8M0W	Investigative	Aldo-keto reductase family 1 member C4 (AKR1C4) affects the oxidation of tetrahydrodeoxycorticosterone.	[5]
Indan-1-ol	DMMLQZJ	Investigative	Aldo-keto reductase family 1 member C4 (AKR1C4) increases the oxidation of Indan-1-ol.	[19]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Aldo-keto reductase family 1 member C4 (AKR1C4).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Aldo-keto reductase family 1 member C4 (AKR1C4).	[11]

23 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 Aldo-keto reductase family 1 member C4 (AKR1C4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aldo-keto reductase family 1 member C4 (AKR1C4).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Aldo-keto reductase family 1 member C4 (AKR1C4).	[3]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[5]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Aldo-keto reductase family 1 member C4 (AKR1C4).	[6]
Gamolenic acid	DMQN30Z	Approved	Gamolenic acid increases the expression of Aldo-keto reductase family 1 member C4 (AKR1C4).	[7]
Diazepam	DM08E9O	Approved	Diazepam decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[8]
Benzbromarone	DMC3YUA	Approved	Benzbromarone decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[5]
Flunitrazepam	DMGR5Z3	Approved	Flunitrazepam decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[8]
Flufenamic Acid	DMC8VNH	Approved	Flufenamic Acid decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[5]
Meclofenamic acid	DM05FXR	Approved	Meclofenamic acid decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[9]
Nitrazepam	DMEGIQ6	Approved	Nitrazepam decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aldo-keto reductase family 1 member C4 (AKR1C4).	[10]
4-Hydroxybenzoicacid	DM3WQNY	Patented	4-Hydroxybenzoicacid decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[9]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[5]
Phenolphthalein	DM5SICT	Withdrawn from market	Phenolphthalein decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Aldo-keto reductase family 1 member C4 (AKR1C4).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Aldo-keto reductase family 1 member C4 (AKR1C4).	[13]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Aldo-keto reductase family 1 member C4 (AKR1C4).	[14]
Caffeic acid phenethyl ester	DMRJKIV	Investigative	Caffeic acid phenethyl ester decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[9]
18beta-Glycyrrhetic acid	DMFMRN8	Investigative	18beta-Glycyrrhetic acid decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[5]
Medazepam	DMNKSX3	Investigative	Medazepam decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[5]
OCTYL_GALLATE	DMXLGUS	Investigative	OCTYL_GALLATE decreases the activity of Aldo-keto reductase family 1 member C4 (AKR1C4).	[9]

References

• [1] 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.
• [2] 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.
• [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] Selective and potent inhibitors of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone. Chem Biol Interact. 2003 Feb 1;143-144:503-13.
• [6] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [7] Antineoplastic effects of gamma linolenic Acid on hepatocellular carcinoma cell lines. J Clin Biochem Nutr. 2010 Jul;47(1):81-90.
• [8] Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines. Biol Pharm Bull. 2002 Apr;25(4):441-5.
• [9] Initro CAPE inhibitory activity towards human AKR1C3 and the molecular basis. Chem Biol Interact. 2016 Jun 25;253:60-5.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [14] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [15] AKR1C4 gene variant associated with low euthymic serum progesterone and a history of mood irritability in males with bipolar disorder. J Affect Disord. 2011 Sep;133(1-2):346-51. doi: 10.1016/j.jad.2011.04.009. Epub 2011 May 12.
• [16] The role of carbonyl reducing enzymes in oxcarbazepine in vitro metabolism in man. Chem Biol Interact. 2014 Sep 5;220:241-7.
• [17] Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action. J Biol Chem. 2004 Mar 12;279(11):10784-95. doi: 10.1074/jbc.M313308200. Epub 2003 Dec 12.
• [18] Retinaldehyde is a substrate for human aldo-keto reductases of the 1C subfamily. Biochem J. 2011 Dec 15;440(3):335-44.
• [19] Expression and kinetic properties of a recombinant 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzyme of human liver. J Biochem. 1995 Aug;118(2):285-90.