Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ6XF74)

• DOT Name: Aromatase (CYP19A1)
• Synonyms: EC 1.14.14.14; CYPXIX; Cytochrome P-450AROM; Cytochrome P450 19A1; Estrogen synthase
• Gene Name: CYP19A1
• Related Disease:
  Aromatase deficiency
  Aromatase excess syndrome
• UniProt ID: CP19A_HUMAN
• PDB ID: 3EQM; 3S79; 3S7S; 4GL5; 4GL7; 4KQ8; 5JKV; 5JKW; 5JL6; 5JL7; 5JL9
• EC Number: 1.14.14.14
• Pfam ID: PF00067
• Sequence:
  MVLEMLNPIHYNITSIVPEAMPAATMPVLLLTGLFLLVWNYEGTSSIPGPGYCMGIGPLI
  SHGRFLWMGIGSACNYYNRVYGEFMRVWISGEETLIISKSSSMFHIMKHNHYSSRFGSKL
  GLQCIGMHEKGIIFNNNPELWKTTRPFFMKALSGPGLVRMVTVCAESLKTHLDRLEEVTN
  ESGYVDVLTLLRRVMLDTSNTLFLRIPLDESAIVVKIQGYFDAWQALLIKPDIFFKISWL
  YKKYEKSVKDLKDAIEVLIAEKRRRISTEEKLEECMDFATELILAEKRGDLTRENVNQCI
  LEMLIAAPDTMSVSLFFMLFLIAKHPNVEEAIIKEIQTVIGERDIKIDDIQKLKVMENFI
  YESMRYQPVVDLVMRKALEDDVIDGYPVKKGTNIILNIGRMHRLEFFPKPNEFTLENFAK
  NVPYRYFQPFGFGPRGCAGKYIAMVMMKAILVTLLRRFHVKTLQGQCVESIQKIHDLSLH
  PDETKNMLEMIFTPRNSDRCLEH
• Function: A cytochrome P450 monooxygenase that catalyzes the conversion of C19 androgens, androst-4-ene-3,17-dione (androstenedione) and testosterone to the C18 estrogens, estrone and estradiol, respectively. Catalyzes three successive oxidations of C19 androgens: two conventional oxidations at C19 yielding 19-hydroxy and 19-oxo/19-aldehyde derivatives, followed by a third oxidative aromatization step that involves C1-beta hydrogen abstraction combined with cleavage of the C10-C19 bond to yield a phenolic A ring and formic acid. Alternatively, the third oxidative reaction yields a 19-norsteroid and formic acid. Converts dihydrotestosterone to delta1,10-dehydro 19-nordihydrotestosterone and may play a role in homeostasis of this potent androgen. Also displays 2-hydroxylase activity toward estrone. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).
• Tissue Specificity: Widely expressed, including in adult and fetal brain, placenta, skin fibroblasts, adipose tissue and gonads.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolic pathways (hsa01100)
  Ovarian steroidogenesis (hsa04913)
• Reactome Pathway:
  Endogenous sterols (R-HSA-211976)
  Defective CYP19A1 causes AEXS (R-HSA-5579030)
  Estrogen biosynthesis (R-HSA-193144)
• BioCyc Pathway: MetaCyc:HS06413-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
Aromatase deficiency	DISMDRRM	Definitive	Autosomal recessive	[1]
Aromatase excess syndrome	DIS1N9UV	Moderate	Autosomal dominant	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Estrone	DM5T6US	Approved	Aromatase (CYP19A1) increases the chemical synthesis of Estrone.	[69]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Aromatase (CYP19A1) increases the Metabolic disorder ADR of Chlorothiazide.	[70]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
(Z)-endoxifen	DMGDOS2	Phase 2	Aromatase (CYP19A1) increases the metabolism of (Z)-endoxifen.	[71]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	Aromatase (CYP19A1) increases the metabolism of 4-ANDROSTENE-3-17-DIONE.	[72]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Aromatase (CYP19A1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aromatase (CYP19A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Aromatase (CYP19A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aromatase (CYP19A1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Aromatase (CYP19A1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aromatase (CYP19A1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Aromatase (CYP19A1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Aromatase (CYP19A1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Aromatase (CYP19A1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Aromatase (CYP19A1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Aromatase (CYP19A1).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Aromatase (CYP19A1).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the activity of Aromatase (CYP19A1).	[15]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Aromatase (CYP19A1).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Aromatase (CYP19A1).	[17]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Aromatase (CYP19A1).	[18]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Aromatase (CYP19A1).	[19]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Aromatase (CYP19A1).	[20]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the activity of Aromatase (CYP19A1).	[21]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the activity of Aromatase (CYP19A1).	[22]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Aromatase (CYP19A1).	[23]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Aromatase (CYP19A1).	[24]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Aromatase (CYP19A1).	[25]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Aromatase (CYP19A1).	[24]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Aromatase (CYP19A1).	[26]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Aromatase (CYP19A1).	[4]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Aromatase (CYP19A1).	[24]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Aromatase (CYP19A1).	[27]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the activity of Aromatase (CYP19A1).	[15]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Aromatase (CYP19A1).	[28]
Fluoxetine	DM3PD2C	Approved	Fluoxetine decreases the activity of Aromatase (CYP19A1).	[29]
Sertraline	DM0FB1J	Approved	Sertraline decreases the activity of Aromatase (CYP19A1).	[29]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of Aromatase (CYP19A1).	[30]
Docetaxel	DMDI269	Approved	Docetaxel decreases the expression of Aromatase (CYP19A1).	[31]
Bezafibrate	DMZDCS0	Approved	Bezafibrate decreases the expression of Aromatase (CYP19A1).	[32]
Melatonin	DMKWFBT	Approved	Melatonin decreases the expression of Aromatase (CYP19A1).	[33]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the activity of Aromatase (CYP19A1).	[34]
Hesperetin	DMKER83	Approved	Hesperetin decreases the activity of Aromatase (CYP19A1).	[35]
Estriol	DMOEM2I	Approved	Estriol decreases the expression of Aromatase (CYP19A1).	[36]
Clotrimazole	DMMFCIH	Approved	Clotrimazole decreases the activity of Aromatase (CYP19A1).	[37]
Trovafloxacin	DM6AN32	Approved	Trovafloxacin decreases the activity of Aromatase (CYP19A1).	[38]
Exemestane	DM9HPW3	Approved	Exemestane decreases the activity of Aromatase (CYP19A1).	[39]
Citalopram	DM2G9AE	Approved	Citalopram decreases the activity of Aromatase (CYP19A1).	[29]
Lamotrigine	DM8SXYG	Approved	Lamotrigine decreases the activity of Aromatase (CYP19A1).	[15]
Amlodipine	DMBDAZV	Approved	Amlodipine decreases the activity of Aromatase (CYP19A1).	[38]
Letrozole	DMH07Y3	Approved	Letrozole decreases the activity of Aromatase (CYP19A1).	[39]
Paroxetine	DM5PVQE	Approved	Paroxetine decreases the activity of Aromatase (CYP19A1).	[29]
Miconazole	DMPMYE8	Approved	Miconazole decreases the activity of Aromatase (CYP19A1).	[37]
Amoxicillin	DMUYNEI	Approved	Amoxicillin increases the expression of Aromatase (CYP19A1).	[40]
Niflumic acid	DMJ3I1Q	Approved	Niflumic acid decreases the expression of Aromatase (CYP19A1).	[24]
Oxcarbazepine	DM5PU6O	Approved	Oxcarbazepine decreases the activity of Aromatase (CYP19A1).	[15]
Luvox	DMJKROX	Approved	Luvox decreases the activity of Aromatase (CYP19A1).	[29]
Fluconazole	DMOWZ6B	Approved	Fluconazole decreases the activity of Aromatase (CYP19A1).	[41]
Oestradiol valerate and dienogest	DMZK0FQ	Approved	Oestradiol valerate and dienogest decreases the expression of Aromatase (CYP19A1).	[16]
FADROZOLE	DM3C5GZ	Approved	FADROZOLE decreases the activity of Aromatase (CYP19A1).	[42]
Anastrozole	DMNP60F	Approved	Anastrozole decreases the activity of Aromatase (CYP19A1).	[39]
Levetiracetam	DMTGDN8	Approved	Levetiracetam decreases the expression of Aromatase (CYP19A1).	[43]
Bifonazole	DM3KN7V	Approved	Bifonazole decreases the activity of Aromatase (CYP19A1).	[37]
Ethosuximide	DMDZ9LT	Approved	Ethosuximide decreases the activity of Aromatase (CYP19A1).	[15]
Tiagabine	DMKSQG0	Approved	Tiagabine decreases the activity of Aromatase (CYP19A1).	[15]
Testolactone	DMVY4GN	Approved	Testolactone decreases the activity of Aromatase (CYP19A1).	[44]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aromatase (CYP19A1).	[45]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Aromatase (CYP19A1).	[46]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Aromatase (CYP19A1).	[47]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Aromatase (CYP19A1).	[48]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the activity of Aromatase (CYP19A1).	[49]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Aromatase (CYP19A1).	[50]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Aromatase (CYP19A1).	[51]
GSK618334	DMJPXZ4	Phase 1	GSK618334 decreases the expression of Aromatase (CYP19A1).	[52]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Aromatase (CYP19A1).	[4]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 decreases the expression of Aromatase (CYP19A1).	[24]
PMID26560530-Compound-35	DMO36RL	Patented	PMID26560530-Compound-35 decreases the activity of Aromatase (CYP19A1).	[53]
FORMESTANE	DMWIDJK	Withdrawn from market	FORMESTANE decreases the activity of Aromatase (CYP19A1).	[54]
YM-511	DM7WDAG	Discontinued in Phase 2	YM-511 decreases the activity of Aromatase (CYP19A1).	[55]
PD-153035	DM7KJTI	Discontinued in Phase 1	PD-153035 decreases the activity of Aromatase (CYP19A1).	[53]
LG100268	DM41RK2	Discontinued in Phase 1	LG100268 decreases the expression of Aromatase (CYP19A1).	[20]
Nimesulide	DMR1NMD	Terminated	Nimesulide decreases the expression of Aromatase (CYP19A1).	[56]
NS398	DMINUWH	Terminated	NS398 decreases the expression of Aromatase (CYP19A1).	[57]
SC-58125	DM874YU	Terminated	SC-58125 decreases the expression of Aromatase (CYP19A1).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Aromatase (CYP19A1).	[59]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate affects the expression of Aromatase (CYP19A1).	[60]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Aromatase (CYP19A1).	[61]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Aromatase (CYP19A1).	[22]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Aromatase (CYP19A1).	[62]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the activity of Aromatase (CYP19A1).	[57]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of Aromatase (CYP19A1).	[63]
U0126	DM31OGF	Investigative	U0126 increases the expression of Aromatase (CYP19A1).	[64]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate decreases the expression of Aromatase (CYP19A1).	[65]
Rutin	DMEHRAJ	Investigative	Rutin decreases the activity of Aromatase (CYP19A1).	[66]
Chrysin	DM7V2LG	Investigative	Chrysin decreases the activity of Aromatase (CYP19A1).	[35]
Daidzein	DMRFTJX	Investigative	Daidzein decreases the expression of Aromatase (CYP19A1).	[47]
Apigenin	DMI3491	Investigative	Apigenin decreases the expression of Aromatase (CYP19A1).	[47]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of Aromatase (CYP19A1).	[47]
[3H]cAMP	DMZRQU7	Investigative	[3H]cAMP increases the expression of Aromatase (CYP19A1).	[64]
Flavone	DMEQH6J	Investigative	Flavone increases the activity of Aromatase (CYP19A1).	[66]
Alpha-naphthoflavone	DMELOIQ	Investigative	Alpha-naphthoflavone increases the expression of Aromatase (CYP19A1).	[67]
TTNPB	DMSABD0	Investigative	TTNPB increases the expression of Aromatase (CYP19A1).	[68]
chlordane	DMMHU8G	Investigative	chlordane increases the expression of Aromatase (CYP19A1).	[68]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Aromatase (CYP19A1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aromatase (CYP19A1).	[58]

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] In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch Toxicol. 2016 Mar;90(3):677-89. doi: 10.1007/s00204-015-1483-z. Epub 2015 Feb 26.
• [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] Trialkyltin compounds bind retinoid X receptor to alter human placental endocrine functions. Mol Endocrinol. 2005 Oct;19(10):2502-16.
• [5] Acetaminophen Modulates the Expression of Steroidogenesis-Associated Genes and Estradiol Levels in Human Placental JEG-3 Cells. Toxicol Sci. 2021 Jan 6;179(1):44-52. doi: 10.1093/toxsci/kfaa160.
• [6] Doxorubicin induces cytotoxicity and miR-132 expression in granulosa cells. Reprod Toxicol. 2020 Sep;96:95-101. doi: 10.1016/j.reprotox.2020.06.001. Epub 2020 Jun 4.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Morphologic effects of estrogen stimulation on 3D MCF-7 microtissues. Toxicol Lett. 2016 Apr 25;248:1-8.
• [9] Estrogen synthesis in human colon cancer epithelial cells. J Steroid Biochem Mol Biol. 1999 Dec 31;71(5-6):223-30.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells. Toxicol Appl Pharmacol. 2013 Jun 1;269(2):176-86.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] An epigenetic disorder may cause aberrant expression of aromatase gene in endometriotic stromal cells. Fertil Steril. 2008 May;89(5 Suppl):1390-6. doi: 10.1016/j.fertnstert.2007.03.078. Epub 2007 Jul 26.
• [14] The Cannabinoid Delta-9-tetrahydrocannabinol Disrupts Estrogen Signaling in Human Placenta. Toxicol Sci. 2020 Oct 1;177(2):420-430. doi: 10.1093/toxsci/kfaa110.
• [15] Inhibition of human aromatase complex (CYP19) by antiepileptic drugs. Toxicol In Vitro. 2008 Feb;22(1):146-53.
• [16] Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E?production in human endometriotic stromal cells in spheroid culture. Fertil Steril. 2012 Feb;97(2):477-82.
• [17] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [19] Cannabidiol (CBD) but not tetrahydrocannabinol (THC) dysregulate in vitro decidualization of human endometrial stromal cells by disruption of estrogen signaling. Reprod Toxicol. 2020 Apr;93:75-82. doi: 10.1016/j.reprotox.2020.01.003. Epub 2020 Jan 14.
• [20] Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells. Biochem Biophys Res Commun. 2000 May 19;271(3):710-3.
• [21] Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination. Toxicol Appl Pharmacol. 2007 Jul 15;222(2):129-40.
• [22] A benzimidazole fungicide, benomyl, and its metabolite, carbendazim, induce aromatase activity in a human ovarian granulose-like tumor cell line (KGN). Endocrinology. 2004 Apr;145(4):1860-9.
• [23] Decreased levels of H3K9ac and H3K27ac in the promotor region of ovarian P450 aromatase mediated low estradiol synthesis in female offspring rats induced by prenatal nicotine exposure as well as in human granulosa cells after nicotine treatment. Food Chem Toxicol. 2019 Jun;128:256-266. doi: 10.1016/j.fct.2019.03.055. Epub 2019 Apr 6.
• [24] Translational studies on aromatase, cyclooxygenases, and enzyme inhibitors in breast cancer. J Steroid Biochem Mol Biol. 2005 May;95(1-5):129-36.
• [25] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [26] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [27] Steroidogenic gene expression in H295R cells and the human adrenal gland: adrenotoxic effects of lindane in vitro. J Appl Toxicol. 2006 Nov-Dec;26(6):484-92.
• [28] Ascorbic acid transported by sodium-dependent vitamin C transporter 2 stimulates steroidogenesis in human choriocarcinoma cells. Endocrinology. 2008 Jan;149(1):73-83.
• [29] Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay. Toxicol In Vitro. 2015 Oct;29(7):1729-35.
• [30] Aromatase in endometriosis and uterine leiomyomata. J Steroid Biochem Mol Biol. 2005 May;95(1-5):57-62.
• [31] Down-regulation of intratumoral aromatase messenger RNA levels by docetaxel in human breast cancers. Clin Cancer Res. 2004 Dec 15;10(24):8163-9.
• [32] Bisphenol A downregulates CYP19 transcription in JEG-3 cells. Toxicol Lett. 2009 Sep 28;189(3):248-52.
• [33] Melatonin inhibits the growth of DMBA-induced mammary tumors by decreasing the local biosynthesis of estrogens through the modulation of aromatase activity. Int J Cancer. 2006 Jan 15;118(2):274-8. doi: 10.1002/ijc.21401.
• [34] Benzofuran- and furan-2-yl-(phenyl)-3-pyridylmethanols: synthesis and inhibition of P450 aromatase. J Enzyme Inhib Med Chem. 2005 Apr;20(2):135-41.
• [35] Inhibition of aromatase activity by flavonoids. Arch Pharm Res. 1999 Jun;22(3):309-12.
• [36] Aflatoxin B1--a potential endocrine disruptor--up-regulates CYP19A1 in JEG-3 cells. Toxicol Lett. 2011 May 10;202(3):161-7.
• [37] Comparative assessment of the inhibition of recombinant human CYP19 (aromatase) by azoles used in agriculture and as drugs for humans. Endocr Res. 2004 Aug;30(3):387-94.
• [38] Cell-based high-throughput screening for aromatase inhibitors in the Tox21 10K library. Toxicol Sci. 2015 Oct;147(2):446-57.
• [39] Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005 Apr 15;11(8):2809-21. doi: 10.1158/1078-0432.CCR-04-2187.
• [40] Modulation of steroidogenic gene expression and hormone production of H295R cells by pharmaceuticals and other environmentally active compounds. Toxicol Appl Pharmacol. 2007 Dec 1;225(2):142-53.
• [41] The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax. Toxicology. 2019 Sep 1;425:152247. doi: 10.1016/j.tox.2019.152247. Epub 2019 Jul 19.
• [42] Synthesis and evaluation of (pyridylmethylene)tetrahydronaphthalenes/-indanes and structurally modified derivatives: potent and selective inhibitors of aldosterone synthase. J Med Chem. 2005 Mar 10;48(5):1563-75.
• [43] Differential effects of antiepileptic drugs on steroidogenesis in a human in vitro cell model. Acta Neurol Scand Suppl. 2009;(189):14-21.
• [44] Aromatase inhibitors in precocious puberty: rationale and experience to date. Treat Endocrinol. 2004;3(3):141-51. doi: 10.2165/00024677-200403030-00002.
• [45] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [46] Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs. Prostate. 2014 Jun;74(8):839-51.
• [47] Phytoestrogens and their low dose combinations inhibit mRNA expression and activity of aromatase in human granulosa-luteal cells. J Steroid Biochem Mol Biol. 2006 Nov;101(4-5):216-25. doi: 10.1016/j.jsbmb.2006.06.021. Epub 2006 Sep 11.
• [48] Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation. Cancer Res. 2009 Jul 1;69(13):5415-23.
• [49] Inhibitory effects of nitric oxide on the expression and activity of aromatase in human granulosa cells. Mol Hum Reprod. 1999 May;5(5):396-401.
• [50] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [51] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [52] Fingolimod interrupts the cross talk between estrogen metabolism and sphingolipid metabolism within prostate cancer cells. Toxicol Lett. 2018 Jul;291:77-85.
• [53] Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue. J Steroid Biochem Mol Biol. 2005 May;95(1-5):17-23.
• [54] Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro. Toxicol In Vitro. 2000 Jun;14(3):227-34.
• [55] Early phase II study of the new aromatase inhibitor YM511 in postmenopausal patients with breast cancer. Difficulty in clinical dose recommendation based on preclinical and phase I findings. Anticancer Res. 2003 Jul-Aug;23(4):3533-42.
• [56] COX-2 inhibitor nimesulide analogs are aromatase suppressors in breast cancer cells. J Steroid Biochem Mol Biol. 2010 Oct;122(4):232-8. doi: 10.1016/j.jsbmb.2010.06.004. Epub 2010 Jun 11.
• [57] Novel sulfonanilide analogues suppress aromatase expression and activity in breast cancer cells independent of COX-2 inhibition. J Med Chem. 2006 Feb 23;49(4):1413-9.
• [58] 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.
• [59] Endocrine disrupting effects of ochratoxin A at the level of nuclear receptor activation and steroidogenesis. Toxicol Lett. 2013 Mar 13;217(3):243-50. doi: 10.1016/j.toxlet.2012.12.018. Epub 2013 Jan 4.
• [60] Effects of single and repeated in vitro exposure of three forms of parabens, methyl-, butyl- and propylparabens on the proliferation and estradiol secretion in MCF-7 and MCF-10A cells. Pharmacol Rep. 2013;65(2):484-93.
• [61] Differential effects of glyphosate and roundup on human placental cells and aromatase. Environ Health Perspect. 2005 Jun;113(6):716-20.
• [62] Organotin exposure stimulates steroidogenesis in H295R Cell via cAMP pathway. Ecotoxicol Environ Saf. 2018 Jul 30;156:148-153.
• [63] Effects of Cyanobacterial Harmful Algal Bloom Toxin Microcystin-LR on Gonadotropin-Dependent Ovarian Follicle Maturation and Ovulation in Mice. Environ Health Perspect. 2023 Jun;131(6):67010. doi: 10.1289/EHP12034. Epub 2023 Jun 21.
• [64] Low-dose bisphenol A activates the ERK signaling pathway and attenuates steroidogenic gene expression in human placental cells. Biol Reprod. 2018 Feb 1;98(2):250-258.
• [65] Dibutyl phthalate impairs steroidogenesis and a subset of LH-dependent genes in cultured human mural granulosa cell in vitro. Reprod Toxicol. 2017 Apr;69:13-18.
• [66] Induction and inhibition of aromatase (CYP19) activity by natural and synthetic flavonoid compounds in H295R human adrenocortical carcinoma cells. Toxicol Sci. 2004 Nov;82(1):70-9.
• [67] The AhR is constitutively activated and affects granulosa cell features in the human cell line KGN. Mol Hum Reprod. 2011 Feb;17(2):104-14.
• [68] Modulation of aromatase activity and mRNA by various selected pesticides in the human choriocarcinoma JEG-3 cell line. Toxicology. 2006 Nov 10;228(1):98-108.
• [69] Steroid signalling in the ovarian surface epithelium. Trends Endocrinol Metab. 2005 Sep;16(7):327-33.
• [70] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.
• [71] The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes. Arch Toxicol. 2018 Mar;92(3):1099-1112.
• [72] A comparison of two human cell lines and two rat gonadal cell primary cultures as in vitro screening tools for aromatase modulation. Toxicol In Vitro. 2012 Feb;26(1):107-18.