Jq. Chen et al., Inhibition of TGF-beta-induced apoptosis by ethinyl estradiol in cultured,precision cut rat liver slices and hepatocytes, CARCINOGENE, 21(6), 2000, pp. 1205-1211
Ethinyl estradiol (EE) is a strong promoter of hepatocarcinogenesis in the
rat. Treatment with EE and other hepatic promoters induces transient growth
stimulation followed by growth inhibition (mitosuppression) in hepatocytes
, Previously, we identified several genes whose transcript levels were incr
eased during EE-induced mitosuppression, including transforming growth fact
or beta (TGF-beta), which inhibits growth and induces apoptosis in hepatocy
tes. Various hepatic promoters, including phenobarbital and several peroxis
omal proliferators, have been shown to inhibit TGF-beta-induced apoptosis i
n rat hepatocytes, The goal of this study was to investigate whether EE is
also an inhibitor of TGF-beta-induced apoptosis in rat hepatocytes. Several
approaches to detect apoptosis were used, including the TUNEL assay, detec
tion of high molecular weight DNA fragmentation by field inversion gel elec
trophoresis and determination of cytosolic cytochrome c levels by western a
nalysis. TGF-beta-induced apoptosis in cultured, precision cut liver slices
and hepatocytes of female rats. EE (less than or equal to 3 mu M) complete
ly inhibited TGF-beta-induced apoptosis in these systems in the absence of
cytotoxicity, These findings add EE to the list of several hepatic promoter
s that both induce TGF-beta while simultaneously inhibiting its ability to
cause apoptosis.