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Phenobarbital induction of α1-acid glycoprotein in primary rat hepatocyte cultures

✍ Scribed by Thierry Fournier; Najet Mejdoubi; Dagui Monnet; Geneviève Durand; Dominique Porquet

Publisher
John Wiley and Sons
Year
1994
Tongue
English
Weight
582 KB
Volume
20
Category
Article
ISSN
0270-9139

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✦ Synopsis

The serum level of rat a,-acid glycoprotein is significantly increased by treatment with phenobarbital, and in uiuo studies have shown that phenobarbital seems to act mainly at the transcriptional level. To show the direct mediating effect of phenobarbital on a,-acid glycoprotein gene expression, we investigated the ability of primary cultured rat hepatocytes to respond to in uitro phenobarbital administration. Phenobarbital increased both a,-acid glycoprotein secretion and corresponding mRNA levels in primary rat hepatocytes cultured on matrigel. Used in combination with interleukin-1, interleukin-6 and dexamethasone, phenobarbital had an additive or synergistic effect on a,-acid glycoprotein synthesis. These results show that (a) phenobarbital acts directly on hepatocytes by increasing a,-acid glycoprotein gene expression and (b) this effect is mediated by a specific mechanism independent of pathways involved in a,-acid glycoprotein induction by interleukin-1, interleukin-6 and glucocorticoids. (HEPATOLOGY 1994;20: 1684-1588.)

Hepatic production of AGP is strongly increased after systemic tissue injury (1, 2). The induction of this response is mediated mainly by soluble cytokines interacting with specific receptors on hepatocytes (3-5). A major role is played by IL-1 and tumor necrosis factor-a, and IL-6 acts synergistically in the induction of AGP (6-11). However, maximal expression of AGP requires the presence of glucocorticoids (12-14) but this does not rule out additional effects of other cytokines, including leukemia inhibitory factor (15, 161, and oncostatin M (18). Recently we showed that phenobarbital, a strong inducer of liver drug-metabolizing enzymes, increases AGP gene expression in uiuo. This effect seems to occur mainly at the transcriptional level

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