C. Wang et al., Diminished energy metabolism and enhanced apoptosis in livers of B6C3F1 mice treated with the antihepatocarcinogen rotenone, MOL C BIOCH, 201(1-2), 1999, pp. 25-32
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.