effects of TCDD in cultured murine hepatoma cells is a rapid, transient increase in Ca2+ influx and a minor, but significant, elevation of activated, membranebound protein kinase C (PKC) (Puga et al., 1992). Increased PKC is associated with induction of several immediate early proto-oncogenes, including c-fos, jun-B, c-jun, and jun-D, and large increases in AP-1 transcription factor activity. Induction of proto-oncogene expression in hepatoma cells by TCDD is independent of AhR or ARNT (Puga et al., 1992).

AhR Signaling Interactions An interesting correlation was recently established between the induction of the multidrug resistance (MDR) gene product, P-glycoprotein, and AhR signaling in primary human hepatocyte cultures (Schuetz et al., 1995). In these studies, induction profiles of mdr mRNA were compared to those for CYP1A1 mRNA. Induction of CYP1A1 mRNA was observed in hepatocyte cultures from 15 different individuals treated with TCDD or 3-methylcholanthrene. However, induction of mdr mRNA was only observed in half of the preparations treated with TCDD, suggesting that TCDD regulates mdr in humans by a mechanism distinct from the classical AhR pathway.

There is a growing body of evidence that AhR-related signaling influences, and is itself influenced by, other signal transduction mechanisms at low concentrations. The toxic effects of TCDD involve disruption of various signal transduction pathways. Signaling interactions explaining the toxic effects of TCDD are discussed below. These involve growth factors and their corresponding receptors, free radicals, protein kinases, and the interaction of TCDD with the estrogen transduction pathway.

Growth Factor In vivo and in vitro evidence suggests that TCDD influences epidermal growth factor (EGF), transforming growth factor (TGF) α_, TGF β_, interleukin (IL) 1β, and tumor necrosis factor (TNF), among others. TGFβ1 exerts an inhibitory effect of TCDD-induced EROD activity in cultured cells (Vogel et al., 1994). Likewise, IL-1β interferes with TCDD induction of CYP1A1 and CYP1A2 via a transcriptional mechanism (Barker et al., 1992). Down-regulation of TCDD-induced CYP1A1 activity has also been demonstrated for other cytokines or growth factors (Jeong et al., 1993). In non-transformed human keratinocytes treated with 10 nM TCDD prior to confluence, TCDD altered both the mRNA and protein concentrations of TGFα, TGFβ2, plasminogen activator inhibitor (PAI)-2, and IL-1β, regulatory proteins known to influence the cellular programming of growth and differentiation in these cells (Gaido and Maness, 1994). However, the effects of TCDD on the signal transduction cascades triggered by these factors are strongly influenced by cell type and by the degree of cellular differentiation and hormonal status. For instance, TCDD decreases binding of EGF in the livers of intact female rats but not in ovariectomized rats, suggesting that the response is dependent on estrogen action (Kohn et al., 1993).



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