BIPHASIC DOSE-RESPONSE RELATIONSHIPS 63mechanism for the phenomenon of autoprotection.48 The protective dose-
stimulated hepatocellular regeneration and tissue repair enable the autopro-
tected animal to recover from the same level of massive injury.48 Nonethe
less, the mechanism of cytochrome P-450 destruction by CC1 4 is of interest.
Although a direct demonstration of *CC1 3 and CC1 302 radicals has been
claimed using spin trapping techniques,13’20’49 50 the precise events leading to
the destruction of cytochrome P-450 by CC1 4 remain elusive. One view
holds that the -CC1 3 free radical directly interacts with the endoplasmic
reticulum and destroys the cytochrome P-450;47’49’50 another view holds that
lipid peroxidation initiated by the -CC1 3 free radical results in the destruc
tion of cytochrome P-450.51 There is evidence that the lipid peroxidation
initiated by the *CC1 3 or CC1 30 2 radicals results in the release of 4-
hydroxynonenol,52 which has been demonstrated to inhibit cytochrome P-
450 mediated mixed-function oxygenase (MFO) activity.53 The demonstra
tion 2854 that phosgene is a metabolite of CC1 4 has raised the possibility that
this reactive metabolite may also be involved in the destruction of cyto
chrome P-450.
POTENTIATION OF HALOMETHANE HEPATOTOXICITY
The enhancement of CC1 4 toxicity by a variety of chemicals has been
observed: phenobarbital,55-58 aliphatic alcohols,59 60 ketones,6162 DDT,63
polychlorinated biphenyls,64 and other experimental manipulations.65-68
Pyrazole,69 vitamin A,70 other halomethanes,71 and complex chemical waste
mixtures 72 are representative examples. 3-Methylcholanthrene protects
against CC1 4 hepatotoxicity.73 74 Treatment with cysteamine, cysteine, or
SKF-525A75 76 —and a number of other chemicals77-80 —afford protection
against CC1 4 hepatotoxicity. Studies also indicate protection by partial hep-
atectomy,81-86 and by an externally supplemented source of energy.87-90
Most, if not all, experimental conditions that potentiate the toxicity of CC1 4
correlate with increased hepatic microsomal cytochrome P-450 content and
with accordingly increased bioactivation of CC1 4 in the liver. Hepatocellular
injury is increased as a consequence of the enhanced production of free-
radical forms of CC1 4 metabolites.
Hepatotoxicity of BrCCl 3 is also known to be potentiated by agents
known to induce drug-metabolizing enzymes of the liver.30 91 92 Hepatotoxic
ity of other halomethanes related to CHC1 3 is also potentiated by other
chemicals. Hepato- and nephrotoxicity of CHC1 3 is potentiated by aliphatic
alcohols,93-95 ketones,96 97 and phenobarbital.32
The widely accepted theory for the mechanism of xenobiotic-induced
enhancement of liver injury caused by CC1 4 is that its bioactivation to *CC1 3
and CC1 302 free radical is increased.12-27 There is evidence for increased
covalent binding of CC1 4 to liver tissue upon bioactivation.121319 Increased