Effects of the tumor promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin -TCDD- on the regulation of growth and inositolphosphate formation in primary rat hepatocytes

The pleiotropic response of hepatocytes towards TCDD includes the interaction with signal transfer pathways via receptors of hormones, e.g. insulin or glucocorticoids, or by activation of protein kinase C (PKC), which is known to regulate the inositoltrisphosphate (IP3) formation. To elucidate possible mechanisms of tumor promotion in vitro, we studied the effects of TCDD after 2 days of treatment in primary cultures of adult rat hepatocytes: DNA synthesis and vasopressin-induced IP3 formation were maximally stimulated by 10high-2M TCDD (1.5 fold); the growth stimulation was dependent on the concentration (10high-7M) of insulin and dexamethasone in the culture media. A short-term activation of PKC by TCDD (10high-12M) was observed with freshly isolated hepatocytes. The results suggest that TCDD in stimulating the growth and IP3 formation of hepatocytes interacts with hormones and that very low concentrations of TCDD, l.e. 2 orders of magnitude below those necessary for the induction of drug metabolizing enzymes, are active. Supported by grants from Deutsche Forschungsgemeinschaft.