Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBDJ6RL)

• DOT Name: Aldo-keto reductase family 1 member D1 (AKR1D1)
• Synonyms: EC 1.3.1.3; 3-oxo-5-beta-steroid 4-dehydrogenase; Delta(4)-3-ketosteroid 5-beta-reductase; Delta(4)-3-oxosteroid 5-beta-reductase
• Gene Name: AKR1D1
• Related Disease: Congenital bile acid synthesis defect 2
• UniProt ID: AK1D1_HUMAN
• PDB ID: 3BUR; 3BUV; 3BV7; 3CAQ; 3CAS; 3CAV; 3CMF; 3COT; 3DOP; 3G1R; 3UZW; 3UZX; 3UZY; 3UZZ
• EC Number: 1.3.1.3
• Pfam ID: PF00248
• Sequence:
  MDLSAASHRIPLSDGNSIPIIGLGTYSEPKSTPKGACATSVKVAIDTGYRHIDGAYIYQN
  EHEVGEAIREKIAEGKVRREDIFYCGKLWATNHVPEMVRPTLERTLRVLQLDYVDLYIIE
  VPMAFKPGDEIYPRDENGKWLYHKSNLCATWEAMEACKDAGLVKSLGVSNFNRRQLELIL
  NKPGLKHKPVSNQVECHPYFTQPKLLKFCQQHDIVITAYSPLGTSRNPIWVNVSSPPLLK
  DALLNSLGKRYNKTAAQIVLRFNIQRGVVVIPKSFNLERIKENFQIFDFSLTEEEMKDIE
  ALNKNVRFVELLMWRDHPEYPFHDEY
• Function: Catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure to yield an A/B cis-ring junction. This cis-configuration is crucial for bile acid biosynthesis and plays important roles in steroid metabolism. Capable of reducing a broad range of delta-(4)-3-ketosteroids from C18 (such as, 17beta-hydroxyestr-4-en-3-one) to C27 (such as, 7alpha-hydroxycholest-4-en-3-one).
• Tissue Specificity: Highly expressed in liver. Expressed in testis and weakly in colon.
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
• 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)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital bile acid synthesis defect 2	DISON1SE	Definitive	Autosomal recessive	[1]

This DOT Affected the Biotransformations of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Aldo-keto reductase family 1 member D1 (AKR1D1) increases the reduction of Progesterone.	[18]
Hydrocortisone	DMGEMB7	Approved	Aldo-keto reductase family 1 member D1 (AKR1D1) increases the reduction of Hydrocortisone.	[19]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	Aldo-keto reductase family 1 member D1 (AKR1D1) increases the reduction of 4-ANDROSTENE-3-17-DIONE.	[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 D1 (AKR1D1).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aldo-keto reductase family 1 member D1 (AKR1D1).	[15]

18 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 D1 (AKR1D1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[13]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[14]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Aldo-keto reductase family 1 member D1 (AKR1D1).	[17]

References

• [1] Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003 Oct;52(10):1494-9. doi: 10.1136/gut.52.10.1494.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [10] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [18] The crystal structure of human Delta4-3-ketosteroid 5beta-reductase defines the functional role of the residues of the catalytic tetrad in the steroid double bond reduction mechanism. Biochemistry. 2008 Aug 12;47(32):8261-70. doi: 10.1021/bi800572s. Epub 2008 Jul 15.
• [19] Human and murine steroid 5-reductases (AKR1D1 and AKR1D4): insights into the role of the catalytic glutamic acid. Chem Biol Interact. 2019 May 25;305:163-170. doi: 10.1016/j.cbi.2019.03.025. Epub 2019 Mar 28.