Table 7.

Mechanisms indicative of genotoxicity, toxicity, and cytotoxicity of OME and their implications for prevention and/or risk of genomic instability.

Activities	Dose/concentration	Study	Study model	Mechanism of action	Prevention/risk for genetic material	References
Genotoxicity	20 and 40 mg/kg	Clinical	Endoscopy biopsy	DNA damage, clastogenic effects, oxidative stress	Genomic instability, genetic risks	[179]
Genotoxicity	20 and 600 mg	Clinical	Human (n = 57)	Interaction between genetic variations, CYP2C19 hydroxylation, and sulfoxidation	Oxidative stress	[180]
Genotoxicity	20 mg/kg	Clinical	Human (n = 33)	Cytogenetic change: micronuclei formation	Genomic instability	[186]
Genotoxicity	20 mg/kg	In vivo	Rats	Cytogenetic alterations, breaks of sister chromatids, micronucleus formation, chromosomal alterations	Genetic instability, cytogenetic damage	[186]
Genotoxicity	—	In vivo	Rodents	Sulfonamide metabolites	Reactivity with DNA	[150]
Genotoxicity	1-100 μM	In vivo	Rats	Activates sulfonamide groups, inhibition of DNA synthesis	DNA damage	[181]
Genotoxicity	30 and 100 mg/kg (p.o.)	In vivo	Rats	DNA synthesis, oxytocin decarboxylase induction	Cell proliferation	[182]
Genotoxicity	30 mg/kg	In vivo	Rats	Micronuclei formation, cellular alteration, cell proliferation	Chromosomal instability, genomic instability	[147]
Genotoxicity	10 and 100 mg/kg	In vivo	Rats	Cell proliferation and replication	Genomic instability	[187]
Genotoxicity	—	In vivo	Rats	Transcriptional changes in the gastric mucosa	Changes in inflammatory regulation genes and immune response	[97]
Genotoxicity	20 ml/kg	In vitro	Rats	Hyperplasia	Genomic instability	[188]
Toxicity	40 mg/kg	Clinical	Case study	Increased ALT and AST levels	Induction of apoptosis	[122]
Toxicity	—	Clinical	Human	Inflammatory, CYP2CI9 enzyme variation, acute nephritis	Genomic instability	[189]
Toxicity	30 and 60 mg/kg	Clinical	—	Microsomal hepatic inhibition, oxidase function, blocking of H+/K+-ATPase system	Oxidative damages	[190]
Toxicity	—	Clinical	Human (n = 2,634)	Interaction between anti-inflammatory and proton pump inhibitors	Apoptosis	[191]
Toxicity	40 mg/kg	Clinical	Human	Neutropenia	Nontoxic effect	[191]
Toxicity	100 μM	In vivo	Rats	Oxidation and toxicity, thiol oxidation, conversion of OME to thiolytic sulfonamides, binding to cysteine residues of H+/K+-ATPase system	Oxidative damages	[192]
Toxicity	0.0001 and 50 mM	In vitro	Polymorphonuclear neutrophils	Apoptosis, sulfhydryl groups	Apoptosis	[4]
Toxicity	0.0001 mM	In vitro	Jurkat cells, lymphomas	Cleavage caspase 3 and PARP	Apoptosis	[123]
Antitumoral neoadjuvant	20 and 40 mg/kg (i.v.)	Clinical	Human (n = 127)	Modulation of tumor acidity, apoptotic cell death	Inhibition of cell proliferation	[124]
Antitumoral	80 mg/kg	Clinical	Human (n = 94)	Synergistic effects with antineoplastic drug	Apoptosis	[160]
Antitumoral	50, 100, and 200 μM	In vitro	Human melanoma cells	Cytotoxic effect	Apoptosis	[87]
Antitumoral	10-40 mg/kg	In vitro, in vivo	Ovary cancer (n = 44) patients	Expression of V-ATPase, inhibition of V-ATPase mRNA protein	Apoptosis and cytotoxicity	[159]
Antitumoral	100 μg/ml	In vitro	CP-A (ATCC CRL-4027) CP-B (ATCC-CRL4028) cells	Inhibits cell cycle growth (arrest cell cycle at G0/G1) by inhibiting miR203a-3p	Induction of apoptosis	[168]
Antitumoral	200 and 300 μM	In vitro	Breast cancer (MCF, SKBR₃ MDA–MB-468) cell lines	Decreases MDA-MB, decreases expression of prometastatic proteins and the expression of C-X-C chemokine receptor 4 (CXCR4)	Prevention of metastasis and inhibition of cell proliferation	[183]
Antitumoral	10 mg/kg	In vivo	Rats	Decreases NO levels, decreases the expression of TNF-α and B catechins	Apoptosis	[184]
Antitumoral	10 and 30 mg/kg	In vitro	HeLa cervical cancer line	Expression of ATPase via SiRNA	Cell proliferation	[70]
Antitumoral	50 and 200 μg/ml	In vitro	Pancreatic cancer cell lines	Interaction with ATPase function regulators, modulation of liposomal transport	Apoptosis	[22]
Antitumoral	100, 200, and 300 μM/l	In vitro	Esophageal adenocarcinoma (KYSE410)	Control intra and extracellular pH, expression of miRNAs	Antiproliferative effect	[165]
Antitumoral	160 μM	In vitro	Melanoma cells	Acidification and alkalinization of tumors, NADPH oxidase dysfunction	Autophagy, oxidative stress	[185]