Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW5YZ7X)

• DOT Name: Extracellular serine/threonine protein kinase FAM20C (FAM20C)
• Synonyms: EC 2.7.11.1; Dentin matrix protein 4; DMP-4; Golgi casein kinase; Golgi-enriched fraction casein kinase; GEF-CK
• Gene Name: FAM20C
• Related Disease:
  Lethal osteosclerotic bone dysplasia
  Vitamin D-dependent rickets, type 2
  Advanced cancer
  Alzheimer disease
  Amelogenesis imperfecta
  Amyotrophic lateral sclerosis type 1
  Arteriosclerosis
  Atherosclerosis
  Bacterial meningitis
  Bipolar depression
  Cardiac failure
  Chronic recurrent multifocal osteomyelitis
  Clear cell renal carcinoma
  Congestive heart failure
  Cutaneous leishmaniasis
  Diabetic retinopathy
  Familial amyotrophic lateral sclerosis
  High blood pressure
  Hyperlipidemia
  Hypophosphatemia
  Inflammatory bowel disease
  Lyme disease
  Male infertility
  Melanoma
  Multiple sclerosis
  Osteoarthritis
  Periodontitis
  Peripheral arterial disease
  Periventricular nodular heterotopia
  Renal cell carcinoma
  Respiratory disease
  Rickets
  Schizophrenia
  Status epilepticus seizure
  Triple negative breast cancer
  Type-1/2 diabetes
  Von willebrand disease
  Focal epilepsy
  Ocular infection
  Skeletal system disorder
  Stroke
  Bone development disease
  Neoplasm
  Amyotrophic lateral sclerosis
  Arrhythmia
  Cardiac disease
  Nervous system disease
• UniProt ID: FA20C_HUMAN
• PDB ID: 5YH3
• EC Number: 2.7.11.1
• Pfam ID: PF06702
• Sequence:
  MKMMLVRRFRVLILMVFLVACALHIALDLLPRLERRGARPSGEPGCSCAQPAAEVAAPGW
  AQVRGRPGEPPAASSAAGDAGWPNKHTLRILQDFSSDPSSNLSSHSLEKLPPAAEPAERA
  LRGRDPGALRPHDPAHRPLLRDPGPRRSESPPGPGGDASLLARLFEHPLYRVAVPPLTEE
  DVLFNVNSDTRLSPKAAENPDWPHAGAEGAEFLSPGEAAVDSYPNWLKFHIGINRYELYS
  RHNPAIEALLHDLSSQRITSVAMKSGGTQLKLIMTFQNYGQALFKPMKQTREQETPPDFF
  YFSDYERHNAEIAAFHLDRILDFRRVPPVAGRMVNMTKEIRDVTRDKKLWRTFFISPANN
  ICFYGECSYYCSTEHALCGKPDQIEGSLAAFLPDLSLAKRKTWRNPWRRSYHKRKKAEWE
  VDPDYCEEVKQTPPYDSSHRILDVMDMTIFDFLMGNMDRHHYETFEKFGNETFIIHLDNG
  RGFGKYSHDELSILVPLQQCCRIRKSTYLRLQLLAKEEYKLSLLMAESLRGDQVAPVLYQ
  PHLEALDRRLRVVLKAVRDCVERNGLHSVVDDDLDTEHRAASAR
• Function: Golgi serine/threonine protein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key role in biomineralization of bones and teeth. Constitutes the main protein kinase for extracellular proteins, generating the majority of the extracellular phosphoproteome. Mainly phosphorylates proteins within the Ser-x-Glu/pSer motif, but also displays a broader substrate specificity. Phosphorylates ERO1A, enhancing its activity which is required to maintain endoplasmic reticulum redox homeostasis and for oxidative protein folding. During endoplasmic reticulum stress, phosphorylates P4HB/PDIA1 which induces a functional switch, causing P4HB to change from an oxidoreductase to a molecular chaperone. This is critical to maintain ER proteostasis and reduce cell death under ER stress. Phosphorylation of P4HB also promotes its interaction with ERN1, leading to reduced activity of ERN1, a key sensor for the endoplasmic reticulum unfolded protein response. Required for osteoblast differentiation and mineralization. Phosphorylates casein as well as a number of proteins involved in biomineralization such as AMELX, AMTN, ENAM and SPP1/OPN. In addition to its role in biomineralization, also plays a role in lipid homeostasis, wound healing and cell migration and adhesion.
• Tissue Specificity: Widely expressed.
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lethal osteosclerotic bone dysplasia	DISM12O0	Definitive	Autosomal recessive	[1]
Vitamin D-dependent rickets, type 2	DISZHFC3	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Amelogenesis imperfecta	DISGYR9E	Strong	Genetic Variation	[5]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[6]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[7]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[7]
Bacterial meningitis	DISRP9SL	Strong	Biomarker	[8]
Bipolar depression	DISA75FU	Strong	Biomarker	[9]
Cardiac failure	DISDC067	Strong	Biomarker	[10]
Chronic recurrent multifocal osteomyelitis	DIST1OU2	Strong	Genetic Variation	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[12]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
Cutaneous leishmaniasis	DISRK7TS	Strong	Biomarker	[13]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[14]
Familial amyotrophic lateral sclerosis	DISWZ9CJ	Strong	Biomarker	[6]
High blood pressure	DISY2OHH	Strong	Biomarker	[7]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[7]
Hypophosphatemia	DIS9DZYF	Strong	Altered Expression	[15]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[16]
Lyme disease	DISO70G5	Strong	Biomarker	[17]
Male infertility	DISY3YZZ	Strong	Biomarker	[18]
Melanoma	DIS1RRCY	Strong	Biomarker	[19]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[20]
Osteoarthritis	DIS05URM	Strong	Biomarker	[21]
Periodontitis	DISI9JOI	Strong	Genetic Variation	[5]
Peripheral arterial disease	DIS78WFB	Strong	Biomarker	[7]
Periventricular nodular heterotopia	DISU3ZRI	Strong	Biomarker	[22]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[12]
Respiratory disease	DISGGAGJ	Strong	Altered Expression	[23]
Rickets	DISH89YF	Strong	Genetic Variation	[24]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Status epilepticus seizure	DISY3BIC	Strong	Biomarker	[25]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[26]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[27]
Von willebrand disease	DIS3TZCH	Strong	Biomarker	[28]
Focal epilepsy	DIS4LY5L	moderate	Biomarker	[29]
Ocular infection	DISTTJES	moderate	Altered Expression	[30]
Skeletal system disorder	DIS5PU87	moderate	Biomarker	[31]
Stroke	DISX6UHX	moderate	Biomarker	[32]
Bone development disease	DISVKAZS	Disputed	Genetic Variation	[33]
Neoplasm	DISZKGEW	Disputed	Biomarker	[34]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[35]
Arrhythmia	DISFF2NI	Limited	Biomarker	[36]
Cardiac disease	DISVO1I5	Limited	Posttranslational Modification	[36]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[37]

3 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 Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[38]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[54]

15 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 Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[39]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[40]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[41]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[42]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[43]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[45]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[46]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[47]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[48]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[49]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[50]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[51]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[52]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[53]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Extracellular serine/threonine protein kinase FAM20C (FAM20C).	[55]

References

• [1] Osteosclerotic bone dysplasia in siblings with a Fam20C mutation. Clin Genet. 2011 Aug;80(2):177-83. doi: 10.1111/j.1399-0004.2010.01516.x. Epub 2010 Jul 23.
• [2] Exome sequencing reveals FAM20c mutations associated with fibroblast growth factor 23-related hypophosphatemia, dental anomalies, and ectopic calcification.J Bone Miner Res. 2013 Jun;28(6):1378-85. doi: 10.1002/jbmr.1850.
• [3] Muscle redox disturbances and oxidative stress as pathomechanisms and therapeutic targets in early-onset myopathies.Semin Cell Dev Biol. 2017 Apr;64:213-223. doi: 10.1016/j.semcdb.2016.08.003. Epub 2016 Aug 12.
• [4] Small Molecule Inhibits Metal-Dependent and -Independent Multifaceted Toxicity of Alzheimer's Disease.ACS Chem Neurosci. 2019 Aug 21;10(8):3611-3621. doi: 10.1021/acschemneuro.9b00216. Epub 2019 Jun 12.
• [5] Periodontal disease and FAM20A mutations.J Hum Genet. 2017 Jul;62(7):679-686. doi: 10.1038/jhg.2017.26. Epub 2017 Mar 16.
• [6] Interplay of Cu,Zn superoxide dismutase and nitric oxide synthase in neurodegenerative processes.IUBMB Life. 2003 Oct-Nov;55(10-11):629-34. doi: 10.1080/15216540310001628717.
• [7] Peripheral artery disease, redox signaling, oxidative stress - Basic and clinical aspects.Redox Biol. 2017 Aug;12:787-797. doi: 10.1016/j.redox.2017.04.017. Epub 2017 Apr 13.
• [8] Protein Oxidation Biomarkers and Myeloperoxidase Activation in Cerebrospinal Fluid in Childhood Bacterial Meningitis.Antioxidants (Basel). 2019 Oct 1;8(10):441. doi: 10.3390/antiox8100441.
• [9] Oxidative Stress and Accelerated Aging in Neurodegenerative and Neuropsychiatric Disorder.Curr Pharm Des. 2018;24(40):4711-4725. doi: 10.2174/1381612825666190115121018.
• [10] Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities.Free Radic Biol Med. 2018 Dec;129:155-168. doi: 10.1016/j.freeradbiomed.2018.09.019. Epub 2018 Sep 15.
• [11] Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes.PLoS Genet. 2016 May 17;12(5):e1006037. doi: 10.1371/journal.pgen.1006037. eCollection 2016 May.
• [12] Ectopic expression of the TERE1 (UBIAD1) protein inhibits growth of renal clear cell carcinoma cells: altered metabolic phenotype associated with reactive oxygen species, nitric oxide and SXR target genes involved in cholesterol and lipid metabolism.Int J Oncol. 2013 Aug;43(2):638-52. doi: 10.3892/ijo.2013.1985. Epub 2013 Jun 12.
• [13] Parasitological and biochemical studies on cutaneous leishmaniasis in Shara'b District, Taiz, Yemen.Ann Clin Microbiol Antimicrob. 2017 Jul 4;16(1):47. doi: 10.1186/s12941-017-0224-y.
• [14] TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation.Mol Metab. 2018 Mar;9:156-167. doi: 10.1016/j.molmet.2018.01.003. Epub 2018 Jan 5.
• [15] Specific ablation of mouse Fam20C in cells expressing type I collagen leads to skeletal defects and hypophosphatemia.Sci Rep. 2017 Jun 15;7(1):3590. doi: 10.1038/s41598-017-03960-x.
• [16] Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence.Exp Biol Med (Maywood). 2012 May;237(5):474-80. doi: 10.1258/ebm.2011.011358. Epub 2012 Mar 22.
• [17] A high-throughput genetic screen identifies previously uncharacterized Borrelia burgdorferi genes important for resistance against reactive oxygen and nitrogen species.PLoS Pathog. 2017 Feb 17;13(2):e1006225. doi: 10.1371/journal.ppat.1006225. eCollection 2017 Feb.
• [18] Reactive oxygen, nitrogen, and sulfur species in human male fertility. A crossroad of cellular signaling and pathology.Biofactors. 2020 Mar;46(2):206-219. doi: 10.1002/biof.1535. Epub 2019 Jun 11.
• [19] Oxidative stress and antioxidants in the pathophysiology of malignant melanoma.Biol Chem. 2019 Apr 24;400(5):589-612. doi: 10.1515/hsz-2018-0327.
• [20] A new role for sphingosine: Up-regulation of Fam20C, the genuine casein kinase that phosphorylates secreted proteins.Biochim Biophys Acta. 2015 Oct;1854(10 Pt B):1718-26. doi: 10.1016/j.bbapap.2015.04.023. Epub 2015 Apr 30.
• [21] Diminished mitochondrial DNA integrity and repair capacity in OA chondrocytes.Osteoarthritis Cartilage. 2009 Jan;17(1):107-13. doi: 10.1016/j.joca.2008.05.009. Epub 2008 Jun 18.
• [22] Treatment of drug-resistant epilepsy in patients with periventricular nodular heterotopia using RNS System: Efficacy and description of chronic electrophysiological recordings.Clin Neurophysiol. 2019 Aug;130(8):1196-1207. doi: 10.1016/j.clinph.2019.04.706. Epub 2019 May 9.
• [23] The role of reactive oxygen and nitrogen species in airway epithelial gene expression.Environ Health Perspect. 1998 Oct;106 Suppl 5(Suppl 5):1197-203. doi: 10.1289/ehp.98106s51197.
• [24] Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications.Eur J Endocrinol. 2016 Feb;174(2):125-36. doi: 10.1530/EJE-15-0515. Epub 2015 Nov 5.
• [25] Novel Use of Responsive Neurostimulation (RNS System) in the Treatment of Super Refractory Status Epilepticus.J Clin Neurophysiol. 2019 May;36(3):242-245. doi: 10.1097/WNP.0000000000000541.
• [26] Systematic network-based discovery of a Fam20C inhibitor (FL-1607) with apoptosis modulation in triple-negative breast cancer.Mol Biosyst. 2016 Jun 21;12(7):2108-18. doi: 10.1039/c6mb00111d.
• [27] Reappraisal of metallothionein: Clinical implications for patients with diabetes mellitus.J Diabetes. 2018 Mar;10(3):213-231. doi: 10.1111/1753-0407.12620. Epub 2018 Jan 5.
• [28] In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion.J Thromb Haemost. 2019 Jun;17(6):866-877. doi: 10.1111/jth.14426. Epub 2019 Apr 5.
• [29] Early detection rate changes from a brain-responsive neurostimulation system predict efficacy of newly added antiseizure drugs.Epilepsia. 2020 Jan;61(1):138-148. doi: 10.1111/epi.16412. Epub 2019 Dec 17.
• [30] Acanthamoeba T4 and T15 genotypes associated with keratitis infections in Italy.Eur J Clin Microbiol Infect Dis. 2009 Jun;28(6):607-12. doi: 10.1007/s10096-008-0682-4. Epub 2008 Dec 18.
• [31] Ancestral roles of the Fam20C family of secreted protein kinases revealed in C. elegans.J Cell Biol. 2019 Nov 4;218(11):3795-3811. doi: 10.1083/jcb.201807041. Epub 2019 Sep 20.
• [32] Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke.Exp Brain Res. 2007 Sep;182(1):1-10. doi: 10.1007/s00221-007-1050-9. Epub 2007 Jul 31.
• [33] A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome.Am J Med Genet A. 2019 Sep;179(9):1866-1871. doi: 10.1002/ajmg.a.61291. Epub 2019 Jul 11.
• [34] Fam20C is under the control of sphingolipid signaling in human cell lines.FEBS J. 2017 Apr;284(8):1246-1257. doi: 10.1111/febs.14052. Epub 2017 Mar 22.
• [35] Repetitive Nerve Stimulation in Amyotrophic Lateral Sclerosis.Chin Med J (Engl). 2018 Sep 20;131(18):2146-2151. doi: 10.4103/0366-6999.240798.
• [36] Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia.Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):9098-9103. doi: 10.1073/pnas.1706441114. Epub 2017 Aug 7.
• [37] Gene expression changes for antioxidants pathways in the mouse cochlea: relations to age-related hearing deficits.PLoS One. 2014 Feb 28;9(2):e90279. doi: 10.1371/journal.pone.0090279. eCollection 2014.
• [38] 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.
• [39] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [40] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [41] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [42] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [43] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [44] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [45] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [46] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [47] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [48] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [49] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [50] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [51] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [52] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [53] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [54] 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.
• [55] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.