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Several types of IFNs were tested for their ability to suppress TCDD-inducible P-450 dependent mixed function oxidase (MFO) system in mouse primary hepatocytes. Mouse IFN-gamma (IFN-G) markedly suppressed EROD activity when added at the same time as TCDD (10 nM). The antagonism of EROD activity by IFN-G exhibited both a dose-(10-100 U/ml) and time-dependence. In contrast, mouse IFN-A/B was only moderately suppressive and only at high concentrations (500 U/ml). Rat IFN-G was even more selective than mouse, whereas human IFN-G had no activity. The species and subtype specificities were confirmed using a monoclonal Ab against mouse IFN-G, which blocked the action of mouse IFN-G, but had no effect on the suppression by either mouse IFN-A/B or rat IFN-G. To confirm the direct effect of IFN-G, liver parenchymal cells were isolated from crude liver cell preparation and it was found that purified parenchymal cells were still sensitive to effects of IFNs. These results indicate that IFNs, particularly IFN-G, can antagonize TCDD-mediated enzyme induction in primary hepatocytes similarly in immune system. Sodium orthovanadate was known as a selective inhibitor of phosphotyrosine phosphatase. In view of protein tyrosine phosphorylation, vanadate was tested in several cell culture systems. Vanadate markedly suppressed EROD activity when added at the same time as TCDD dose- and timedependently in mouse primary hepatocytes. TCDD-induced inhibition of T-dependent antibody formation in mouse splenocytes was also reversed by sodium orthovanadate. As another system, human malaria culture system in human RBC was tested. In both synchronized and unsynchronized malaria parasites, TCDD showed a growth stimulation even though RBC did not have nucleus and Ah receptor dependent gene turn-on. Sod. orthovanadate also compensated TCDD-induced stimulation of malaria growth. By above results in three different culture model systems, it could be assumed that sodium orthovanadate act as a real antagonist against TCDD through a common mechanism with TCDD.
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