Journal Article

ACCELERATED PAPER: Inhibition of gap junctional intercellular communication by barbiturates in long-term primary cultured rat hepatocytes is correlated with liver tumour promoting activity

Ping Ren and Randall J. Ruch

in Carcinogenesis

Volume 17, issue 10, pages 2119-2124
Published in print October 1996 | ISSN: 0143-3334
Published online October 1996 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.10.2119
ACCELERATED PAPER: Inhibition of gap junctional intercellular
                    communication by barbiturates in long-term primary cultured rat hepatocytes is
                    correlated with liver tumour promoting activity

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Rodent liver tumor formation can be promoted by certain barbiturates and this may involve their ability to inhibit hepatocyte gap junctional intercellular communication (GJIC). In order to address the mechanisms and specificity of action of barbiturates on hepatocyte gap junctions, we have compared the effects of liver tumor-promoting barbiturates (phenobarbital, sodium barbital and amobar-bital: PB, SB and AB, respectively) and a non-liver tumor-promoting barbiturate (barbituric acid: BA) on primary cultured rat hepatocyte GJIC and connexin32 (Cx32) expression after short (1–24 h) and long (2–14 days) treatment GJIC was evaluated by fluorescent dye microin-jection (dye-coupling); Cx32 expression was monitored by Northern blot, Western blot and immunohistochemistry. Both parameters were maintained at high levels over 14 days by coculture of the cells with WB-F344 rat liver epithelial cells in the presence of dexamethasone. Treatment with PB (2 mM) for 1 h sharply reduced dye-coupling from ∼90–30%, but the cells fully recovered by 24 h. No inhibition was seen with the other barbiturates over this 1-day treatment period. Longer treatments (2–14 days) with the promoters PB, SB and AB, however, gradually reduced hepatocyte dye-coupling to ∼30–50%. The non-promoter, BA, did not affect hepatocyte GJIC. These decreases in hepatocyte dye-coupling occurred without changes in Cx32 or gap junction expression. Dye-coupling of WB-F344 cells and expression of their predominant gap junction protein, connexin43 (Cx43), were also not affected. Thus, the inhibition of GJIC was specific to liver tumor promoting barbiturates in hepatocytes, was time-dependent and was not due to altered Cx32 expression.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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