title: Okadaic acid and dinophysis toxin 2 have differential toxicological effects in hepatic cell lines inducing cell cycle arrest, at G0/G1 or G2/M with aberrant mitosis depending on the cell line.
abstract: Okadaic acid is one of the toxins responsible for the human intoxication known as diarrhetic shellfish poisoning, which appears after the consumption of contaminated shellfish. The main diarrhetic shellfish poisoning toxins are okadaic acid, dinophysistoxin-1, -2, and -3. In vivo, after intraperitoneal injection, dinophysistoxin-2 is approximately 40% less toxic than okadaic acid in mice. The cytotoxic and genotoxic effect of okadaic acid varies very significantly in different cell lines, so similar responses could be expected for dinophysistoxin-2. In order to determine whether this was the case, we studied the effect of okadaic acid and dinophysistoxin-2 in two hepatic cell lines (HepG2 and Clone 9). The cytotoxicity of these toxins, as well as their effects on the cell cycle and its regulation on both cell lines, were determined. Okadaic acid and dinophysistoxin-2 resulted to be equipotent in clone 9 cultures, while okadaic acid was more potent than dinophysistoxin-2 in HepG2 cell cultures. Both toxins had opposite effects on the cell cycle; they arrested the cell cycle of clone 9 cells in G2/M inducing aberrant mitosis while arresting the cell cycle of HepG2 in G0/G1. When the effect of the toxins on p53 subcellular distribution was studied, p53 was detected in the nuclei of both cell types. The effect of the toxins on the gene expression of cyclins and cyclin-dependent kinases was different for both cell lines. The toxins induced an increase in gene expression of cyclins A, B, and D in clone 9 cells while they induced a decrease in cyclins A and B in HepG2 cells. They also induced a decrease in cyclin-dependent kinase 1 in HepG2 cells.
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, 27002 Lugo, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Rubiolo
authors.forename: H
authors.initials: H
authors.lastname: López-Alonso
authors.forename: F V
authors.initials: FV
authors.lastname: Vega
authors.forename: M R
authors.initials: MR
authors.lastname: Vieytes
authors.forename: L M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016213:Cyclins / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008938:Mitosis / Q000187:drug effects; D019319:Okadaic Acid / Q000633:toxicity* / Q000031:analogs & derivatives; D011714:Pyrans / Q000633:toxicity*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016213:Cyclins; D011714:Pyrans; D016159:Tumor Suppressor Protein p53; D019319:Okadaic Acid; D016203:CDC2 Protein Kinase; C076221:dinophysistoxin 2