Diminished energy metabolism and enhanced apoptosis in livers of B6C3F1 mice treated with the antihepatocarcinogen rotenone

Rotenone decreases the incidence of hepatocellular carcinoma and lowers rat es of hepatocellular proliferation. In an effort to delineate mechanisms in volved, the in vivo effect of rotenone on liver mitochondrial metabolism, a poptotic machinery as well as elements of the hepatic signal transduction p athways were investigated. Mitochondria from livers of male B6C3F1 mice fed a standard diet containing 600 ppm rotenone for 7 days were uncoupled or i nhibited when succinate or glutamate plus malate were used as the substrate , respectively. These livers also showed a significant increase in apoptosi s compared with control livers. Furthermore, rotenone increased the express ion of c-myc mRNA to 5-fold of control values within 3 days, an effect whic h was still observed (3-fold) after 7 days. Levels of p53 mRNA were also in creased 3-fold after 1 day, but declined to control levels by 7 days. Roten one also caused a transient, yet marked increase in liver particulate glyce raldehyde phosphate dehydrogenase (GAPDH) protein expression, while it did not alter the expression of the cytosolic form of the enzyme. Conversely, m RNA of the proto-oncogene H-ras showed a decline of 35% after 3 days of rot enone treatment, and remained diminished for the duration of the experiment . These data suggest that rotenone may act as an anticancer agent by dimini shing mitochondrial bioenergetics which prevents basal hepatocyte prolifera tion and lowers the threshold for liver cells with DNA damage to undergo ap optosis.