Current objectives include assessment of the effects of hepatic tumor promoters and antipromoters on components of the plasma membrane. Current emphasis is on effects of the compounds on protein kinase C and inositide-specific phospholipase C. Previous studies had indicated that di-(2-ethylhexyl) phthalate (DEHP), which is reportedly an antipromotor for rat liver tumors, inhibits protein kinase C in vitro. In extensions of these studies we have found that DEHP non-competitively prevents the activation of protein kinase C by calcium and phosphatidyl serine. This interference results from the binding of DEHP to the regulatory subunit of the kinase. The phosphorylation of proteins such as protamine) that is not under the control of the calcium-responsive subunit is not inhibited by DEHP. The net result is a change in the substrate specificity of the enzyme. DEHP also will displace the strongly tumor-promoting phorbol diesters from protein kinase C (which serves as a phorbol ester receptor).
