Previous studies have shown that "
xenobiotic" compounds such as the
environmental pollutant alpha-hexachlorocyclohexane (
alpha-HCH) and the synthetic sex
steroid cyproterone acetate (CPA) induce growth of rat liver by
hypertrophy and
hyperplasia. After withdrawal of the growth stimuli, liver
hypertrophy was usually found to be readily reversible. Conflicting observations were made concerning the fate of liver
hyperplasia: hepatic
hyperplasia persisted when induced by
alpha-HCH but was found to be partially reversible when induced by CPA. The present study confirms the reversibility of hepatic
hyperplasia induced by CPA in rats: about 30% of liver
DNA present at maximal liver enlargement disappeared within 6 days after cessation of CPA treatment. Simultaneously, a dramatic increase in the rate of cell elimination by apoptosis was found.
Glutamate-
pyruvate transaminase and
alkaline phosphatase in serum did not show major increases, suggesting that cell death was not due to lytic membrane damage. Furthermore, if treatment with CPA was continued or resumed, the enhanced
DNA content persisted and the number of apoptotic bodies was greatly reduced. These observations suggest that the occurrence of cell death is due to withdrawal of the growth stimulus CPA. It may reflect a regulatory phenomenon serving to maintain homeostasis of cell number. Further studies showed that CPA is rapidly eliminated from rat liver and serum: t 1/2 in the liver is about 11 h. In contrast,
alpha-HCH was previously found to be eliminated more slowly: t 1/2 approximately 144 h. The present study revealed that
alpha-HCH, CPA and
nafenopin lower the number of apoptotic bodies. This suggests that inducers of liver growth can inhibit hepatocellular death by apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)