LIVER-CELL PROLIFERATION INDUCED BY NAFENOPIN AND CYPROTERONE-ACETATEIS NOT ASSOCIATED WITH INCREASES IN ACTIVATION OF TRANSCRIPTION FACTORS NF-KAPPA-B AND AP-1 OR WITH EXPRESSION OF TUMOR-NECROSIS-FACTOR-ALPHA

Our previous studies have shown a different pattern of immediate early gene and growth factor gene expression between compensatory liver reg eneration occurring after cell loss/death and direct hyperplasia induc ed by primary mitogens. In the present study, modifications in the act ivation of two transcription factors, NF-kappa B and AP-1; steady-stat e levels of tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRN A); and induction of the inducible nitric oxide synthase (iNOS) were e xamined in rat liver during different types of cell proliferation. Com pensatory regeneration was induced in male Wistar rats by partial hepa tectomy of two thirds (PH) or a necrogenic dose of CCl4 (2 mL/kg), whe reas direct hyperplasia was induced by a single administration of the primary mitogens lead nitrate (LN, 100 mu mol/kg), cyproterone acetate (CPA, 60 mg/kg), or nafenopin (NAF, 200 mg/kg). Liver regeneration af ter treatment with CCl4 was associated with an increase in steady-stat e levels of TNF-alpha mRNA, activation of NF-kappa B and AP-1, and ind uction of iNOS. A strong and prolonged activation of NF-kappa B but no t of AP-1 was observed in LN-induced hyperplasia. LN also induced an i ncrease in hepatic levels of TNF-alpha and iNOS mRNA. On the other han d, direct hyperplasia induced by two other primary mitogens, NAF and C PA, occurred in the complete absence of modifications in the hepatic l evels of TNF-alpha mRNA, activation of NF-kappa B and AP-1, or inducti on of iNOS, although the number of hepatocytes entering S phase 18 to 24 hours after NAF was similar to that seen after PH. These results ad d further support to the hypothesis that cell proliferation occurring in the absence of cell loss/death may be triggered by unknown signalin g pathways different from those responsible for the transition of hepa tocytes from G0 to G1 after PH or cell necrosis.