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.