Phenobarbital specifically reduces gap junction protein mRNA level in rat liver

Abstract

The gene expression of liver major gap junction (GJ) protein was studied in rats systemically administered phenobarbital, a rat liver tumor promoter. Using a GJ protein cDNA and northern blot analysis, the level of GJ protein mRNA in liver was observed to be markedly reduced at 4 and 11 wk of phenobarbital exposure (0.1% in drinking water). However, the level of GJ protein mRNA was not altered in kidney at 11 wk of exposure. In liver, phenobarbital did not induce expression of the neoplasm-associated marker genes glutathione S-transferase (placental form) and gamma-glutamyltranspeptidase, while in kidney the observed expression of these genes was not changed. These in vivo results indicate that phenobarbital reduces GJ protein gene expression specifically in rat liver without altering expression of genes often altered during liver carcinogenesis, and they support assigning a role for the impairment of gap junctional intercellular communication in phenobarbital-mediated liver tumor promotion.

Sequential changes in intercellular junctions between hepatocytes during the course of acute liver injury and restoration after thioacetamide treatment

“…Thus, the hepatocyte response against TAA-induced injury could be divided into three phases regarding changes in GJs: an acute functional response; a response by focal reduction in the number of GJs; and response cell proliferation. The first two phenomena are consistent with the idea that there are two types of mechanisms for the regulation of GJ against liver injury [SJ: short-term regulation by closing channels [16], and long-term regulation by reducing synthesis and assembly of GJs [5,18]. Small molecules, including second messengers such as cAMP [10], calcium ions and IP 3 [12], can be transferred between neighbouring hepatocytes via GJ channels [15].…”

The Interplay between Epigenetics and Gap Junctional Intercellular Communication

“…[115][116][117][118][119][120] This was associated with abnormal frequency and size of gap junctions on the hepatocyte membrane surface, 121 decreased Cx32 immunoreactivity 115,118,119,122 and aberrant Cx32 localization, 117 whereas Cx26 expression was not affected. 115,118,119 Both unchanged 118,120 and decreased 123,124 hepatic Cx32 mRNA levels were reported in phenobarbital-treated rodents. Interestingly, phenobarbital specifically reduced Cx32 protein production in centrolobular hepatocytes of male rodent liver, 115,118,119 which is the acinar area where the phenobarbital-induced expression of CYP450BII1/2 is mostly manifested.…”

Dye and electric coupling between osteoblast-like cells in culture

“…Phenobarbital, another anticonvulsant, is known to inhibit intercellular communication between mouse hepatocytes [32,33] and in two renal epithelial cell lines [53]. In the rat liver, this effect developed within hours and was found to occur at the mRNA level [54], which may point to a drug effect on protein biosynthesis. In cultured OB, carbamazepine and phenytoin were observed to affect gap junction permeability within 2-4 minutes after the application of the drug, pointing to a direct effect of the anticonvulsants on gap junction channels.…”