72 BIOLOGICAL EFFECTS OF LOW LEVEL EXPOSURES
Figure 4.5. Proposed mechanism for phenobarbital-induced potentiation of
CCI4-hepatotoxicity in the absence of increased lethality. Normal liver
response to a low-dose CCI4 injury is not abrogated by phenobarbital +
CCI4 interaction. Instead, the early phase of cell division is postponed (from
the normal 6 hr to 24 hr). Enhanced putative mechanisms, such as
increased bioactivation of CCI4 and resultant increased lipid peroxidation,
are responsible for the increased infliction of Stage I injury. Because
hepatocellular regeneration and tissue repair processes continue, albeit a
bit later than normal, these hormetic mechanisms permit tissue restoration,
resulting in recovery from the enhanced liver injury. This mechanism
explains the remarkable recovery from phenobarbital-induced
enhancement of CCI4 liver injury. A remarkably enhanced liver injury by
phenobarbital is of no real consequence to the animal’s survival because
depletion of cellular energy does not occur with this interaction, which
permits hormetic mechanisms to restore hepatolobular architecture,
resulting in complete recovery.and restoration of hepatolobular architecture. The prolongation of these
normal responses of the liver is a consequence of the enhanced liver injury,
inflicted by the enhanced putative injurious mechanisms. The hypothesis
that suppression of hepatocellular regeneration and tissue repair leads to the
progression of liver injury was experimentally validated in a partial hepatec-
tomy model.8184’86
3 H-Thymidine incorporation into nuclear DNA and the labeling index, as
evidenced by autoradiography of liver sections, were significantly increased
in rats maintained on normal diet at 1 to 2 hr after CC1 4 administration (100