Changes in progesterone binding and metabolism in liver microsomes from persistent hepatocyte nodules and hepatomas...

Hepatocyte nodules that persist throughout chemical carcinogenesis are linked to carcinomas both as one site at which hepatomas are seen to arise and as a tissue which shows more than a dozen significant protein changes also found in liver cancers. In view of the differential stimulus to growth of these persistent nodules by progesterone, progesterone metabolism and binding to the microsomes of nodules and hepatomas were studied. Progesterone metabolizing enzyme activities in nodule microsomes showed striking shifts with a 42% decrease in 16 alpha-hydroxylase activity and a 2- to 3-fold increase in 6 beta-hydroxylase activity compared to control levels. Hepatomas had a dramatic 20-fold increase relative to nodules or controls in the reductive pathway for progesterone metabolism as measured by delta 4-5 alpha-hydrogenase activity. The rate and saturation of the specific binding of progesterone to microsomes of nodules and liver cancers were significantly decreased when compared either to the tissue surrounding the nodules or to their respective control microsomes. This change in progesterone binding of nodular microsomes may relate to an altered balance of progesterone content and its metabolites in the nodular cells or to alterations in the microsomal membrane binding site. The functional significance of reduced binding of progesterone for liver carcinogenesis is thus open to further inquiry.