THE RODENT NONGENOTOXIC HEPATOCARCINOGEN NAFENOPIN SUPPRESSES APOPTOSIS PREFERENTIALLY IN NON-CYCLING HEPATOCYTES BUT ALSO ELEVATES CDK4, ACELL-CYCLE PROGRESSION FACTOR

Rodent non-genotoxic hepatocarcinogens such as nafenopin suppress spon taneous and transforming growth factor pi (TGF beta(1))-induced rat he patocyte apoptosis as well as inducing DNA synthesis, We wished to det ermine if these two processes are associated. In primary rat hepatocyt es, nafenopin suppressed apoptosis from 1.9 to 0.63% but more apoptoti c bodies were bromodeoxyuridine (BrdU)-labelled (0.35%) than predicted statistically from a random distribution of apoptosis within the cycl ing and non-cycling populations (0.10%), In contrast, TGF beta(1) indu ced hepatocyte apoptosis (7.8%) but fewer hepatocytes were BrdU-labell ed (0.29%) than predicted (0.82%). Western blot analyses showed that n afenopin and TGF beta(1) had opposing effects on cyclin-dependent kina se 4 (CDK4) protein: nafenopin elevated CDK4 compared with controls, w hereas TGF beta(1) caused a reduction. These data suggest that nongeno toxic hepatocarcinogens suppress apoptosis in the non-cycling populati on of hepatocytes and elevate CDK4 levels, possibly allowing potential ly tumourigenic cells to enter the cell cycle.