Altered expression of connexin43 in the inhibition of gap junctional intercellular communication by chlorohydroxyfuranones in WB-F344 rat liver epithelial cells. 2006

Pasi Hakulinen, and Elina Rintala, and Jorma Mäki-Paakkanen, and Hannu Komulainen
National Public Health Institute, Laboratory of Toxicology, P.O.B. 95, FI-70701 Kuopio, Finland. pasi.hakulinen@ktl.fi

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA), and 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF) promote foci formation in the two-stage cell transformation assay in vitro. These chlorohydroxyfuranones (CHFs) and their structural congener 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) inhibit gap junctional intercellular communication (GJIC) in Balb/c 3T3 mouse fibroblast cells. In the present study, the effects of MX, MCA, CMCF, and MCF on GJIC were evaluated in liver cells (WB-F344 rat liver epithelial cells), the target cells of MX-induced carcinogenicity, using the scrape-loading dye transfer technique. The CHFs inhibited GJIC after 1 h exposure in a concentration-dependent fashion. The order of potency was MX>CMCF approximately MCA>MCF. In terms of the lowest observed effective concentrations, the difference in the potency was about 27-fold (MX 1.875 microM, MCF 50 microM). After a prolonged exposure period (12 h), the inhibition of GJIC by MX and CMCF remained stable, but MCA and MCF exhibited increasing inhibitory effects. After removal of the CHFs, the GJIC slowly recovered. At the transcriptional level, CHFs caused essentially no change in the level of connexin43 (Cx43) mRNA. Preincubation of cells with the protein kinase C (PKC) inhibitor did not modify the response, but the specific MEK 1 inhibitor PD98059 decreased substantially the inhibition of GJIC by all four CHFs. Activation of the mitogen-activated protein kinases (MAPKs) signaling pathway was necessary for inhibition of GJIC. CHFs did not increase the basal phosphorylation state of the Cx43 protein, but all CHFs caused a concentration-dependent degradation of the Cx43 protein. The results indicate that all the studied CHFs inhibit GJIC in WB-F344 cells by altering Cx43 expression.

UI MeSH Term Description Entries
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011493 Protein Kinase C An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters. Calcium Phospholipid-Dependent Protein Kinase,Calcium-Activated Phospholipid-Dependent Kinase,PKC Serine-Threonine Kinase,Phospholipid-Sensitive Calcium-Dependent Protein Kinase,Protein Kinase M,Calcium Activated Phospholipid Dependent Kinase,Calcium Phospholipid Dependent Protein Kinase,PKC Serine Threonine Kinase,Phospholipid Sensitive Calcium Dependent Protein Kinase,Phospholipid-Dependent Kinase, Calcium-Activated,Serine-Threonine Kinase, PKC
D011916 Rats, Inbred F344 An inbred strain of rat that is used for general BIOMEDICAL RESEARCH purposes. Fischer Rats,Rats, Inbred CDF,Rats, Inbred Fischer 344,Rats, F344,Rats, Inbred Fisher 344,CDF Rat, Inbred,CDF Rats, Inbred,F344 Rat,F344 Rat, Inbred,F344 Rats,F344 Rats, Inbred,Inbred CDF Rat,Inbred CDF Rats,Inbred F344 Rat,Inbred F344 Rats,Rat, F344,Rat, Inbred CDF,Rat, Inbred F344,Rats, Fischer
D002450 Cell Communication Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. Cell Interaction,Cell-to-Cell Interaction,Cell Communications,Cell Interactions,Cell to Cell Interaction,Cell-to-Cell Interactions,Communication, Cell,Communications, Cell,Interaction, Cell,Interaction, Cell-to-Cell,Interactions, Cell,Interactions, Cell-to-Cell
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D004847 Epithelial Cells Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells. Adenomatous Epithelial Cells,Columnar Glandular Epithelial Cells,Cuboidal Glandular Epithelial Cells,Glandular Epithelial Cells,Squamous Cells,Squamous Epithelial Cells,Transitional Epithelial Cells,Adenomatous Epithelial Cell,Cell, Adenomatous Epithelial,Cell, Epithelial,Cell, Glandular Epithelial,Cell, Squamous,Cell, Squamous Epithelial,Cell, Transitional Epithelial,Cells, Adenomatous Epithelial,Cells, Epithelial,Cells, Glandular Epithelial,Cells, Squamous,Cells, Squamous Epithelial,Cells, Transitional Epithelial,Epithelial Cell,Epithelial Cell, Adenomatous,Epithelial Cell, Glandular,Epithelial Cell, Squamous,Epithelial Cell, Transitional,Epithelial Cells, Adenomatous,Epithelial Cells, Glandular,Epithelial Cells, Squamous,Epithelial Cells, Transitional,Glandular Epithelial Cell,Squamous Cell,Squamous Epithelial Cell,Transitional Epithelial Cell
D005419 Flavonoids A group of phenyl benzopyrans named for having structures like FLAVONES. 2-Phenyl-Benzopyran,2-Phenyl-Chromene,Bioflavonoid,Bioflavonoids,Flavonoid,2-Phenyl-Benzopyrans,2-Phenyl-Chromenes,2 Phenyl Benzopyran,2 Phenyl Benzopyrans,2 Phenyl Chromene,2 Phenyl Chromenes
D005663 Furans Compounds with a 5-membered ring of four carbons and an oxygen. They are aromatic heterocycles. The reduced form is tetrahydrofuran. Tetrahydrofurans
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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