Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKBH52X)

• DOT Name: Metallothionein-1A (MT1A)
• Synonyms: MT-1A; Metallothionein-IA; MT-IA
• Gene Name: MT1A
• UniProt ID: MT1A_HUMAN
• Pfam ID: PF00131
• Sequence:
  MDPNCSCATGGSCTCTGSCKCKECKCTSCKKSCCSCCPMSCAKCAQGCICKGASEKCSCC
  A
• Function: Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
• KEGG Pathway: Mineral absorption (hsa04978)
• Reactome Pathway: Metallothioneins bind metals (R-HSA-5661231)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Caffeine	DMKBJWP	Approved	Metallothionein-1A (MT1A) increases the Hepatotoxicity ADR of Caffeine.	[27]
Auranofin	DMWE2N4	Approved	Metallothionein-1A (MT1A) increases the Diarrhoea (excl infective) ADR of Auranofin.	[27]
Heme	DMGC287	Investigative	Metallothionein-1A (MT1A) decreases the response to substance of Heme.	[28]

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 Metallothionein-1A (MT1A).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Metallothionein-1A (MT1A).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Metallothionein-1A (MT1A).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Metallothionein-1A (MT1A).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Metallothionein-1A (MT1A).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Metallothionein-1A (MT1A).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Metallothionein-1A (MT1A).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Metallothionein-1A (MT1A).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Metallothionein-1A (MT1A).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Metallothionein-1A (MT1A).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Metallothionein-1A (MT1A).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Metallothionein-1A (MT1A).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Metallothionein-1A (MT1A).	[11]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Metallothionein-1A (MT1A).	[12]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Metallothionein-1A (MT1A).	[13]
Benzoic acid	DMKB9FI	Approved	Benzoic acid increases the expression of Metallothionein-1A (MT1A).	[13]
Salicyclic acid	DM2F8XZ	Approved	Salicyclic acid increases the expression of Metallothionein-1A (MT1A).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Metallothionein-1A (MT1A).	[14]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Metallothionein-1A (MT1A).	[15]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Metallothionein-1A (MT1A).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Metallothionein-1A (MT1A).	[18]
Arecoline	DMFJZK3	Phase 1	Arecoline increases the expression of Metallothionein-1A (MT1A).	[19]
Benzylcinnamate	DMD7Z3H	Patented	Benzylcinnamate increases the expression of Metallothionein-1A (MT1A).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Metallothionein-1A (MT1A).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Metallothionein-1A (MT1A).	[22]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Metallothionein-1A (MT1A).	[23]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Metallothionein-1A (MT1A).	[24]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Metallothionein-1A (MT1A).	[25]
hydroxycitronellal	DMFHCV9	Investigative	hydroxycitronellal increases the expression of Metallothionein-1A (MT1A).	[13]
Genistein-7-glucoside	DMMLNTW	Investigative	Genistein-7-glucoside increases the expression of Metallothionein-1A (MT1A).	[26]

References

• [1] 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.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Expression pattern of cisplatin-induced metallothionein isoforms in squamous cell carcinoma. Anticancer Res. 2003 Jan-Feb;23(1A):299-303.
• [4] Human drug metabolism genes in parathion-and estrogen-treated breast cells. Int J Mol Med. 2007 Dec;20(6):875-81.
• [5] Blood metallothionein transcript as a biomarker for metal sensitivity: low blood metallothionein transcripts in arsenicosis patients from Guizhou, China. Environ Health Perspect. 2007 Jul;115(7):1101-6.
• [6] Arsenic trioxide (ATO) influences the gene expression of metallothioneins in human glioblastoma cells. Biol Trace Elem Res. 2012 Dec;149(3):331-9.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Gene expression changes in human small airway epithelial cells exposed to Delta9-tetrahydrocannabinol. Toxicol Lett. 2005 Aug 14;158(2):95-107.
• [9] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [10] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [13] A new in vitro method for identifying chemical sensitizers combining peptide binding with ARE/EpRE-mediated gene expression in human skin cells. Cutan Ocul Toxicol. 2010 Sep;29(3):171-92.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [16] Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 2009 Mar 4;28(5):523-32.
• [17] 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.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] The upregulation of metallothionein-1 expression in areca quid chewing-associated oral squamous cell carcinomas. Oral Oncol. 2008 Feb;44(2):180-6.
• [20] Cadmium induces transcription independently of intracellular calcium mobilization. PLoS One. 2011;6(6):e20542.
• [21] 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.
• [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] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [24] Zinc protects HepG2 cells against the oxidative damage and DNA damage induced by ochratoxin A. Toxicol Appl Pharmacol. 2013 Apr 15;268(2):123-31.
• [25] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [26] Water-soluble genistin glycoside isoflavones up-regulate antioxidant metallothionein expression and scavenge free radicals. J Agric Food Chem. 2006 May 31;54(11):3819-26.
• [27] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [28] Metallothionein protects retinal pigment epithelial cells against apoptosis and oxidative stress. Exp Eye Res. 2002 Jan;74(1):83-92.