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 the plasma membrane. Current emphasis is on effects of the compounds on protein kinase C and inositide-specific phospholipase C. Phorbol diesters are traditionally used as biochemical tools in the study of activation, translocation and down-regulation of protein kinase C. but give misleading results when liver tissue or hepatocytes are studied. We have examined the rapid metabolism of the phorbol diesters in hepatocyte cultures. While some of the metabolites are effectively inert (as has been assumed for all the metabolites), other hepatic metabolites bind to the plasma membrane and to protein kinase C even more tightly than do the parent phorbol diesters. We are presently concerned with identification of the active metabolites, which appear to be more highly oxidized than the simple hydrolysis products formed in most other tissues. These metabolites are readily formed either hepatocyte suspensions of liver slices, and are not rapidly eliminated from the cells.
