We have measured liver
heme oxygenase, a
heat shock protein known to be increased under conditions of oxidative stress, to obtain additional evidence for an oxidative stress mechanism in hepatic uroporphyria induced by
hexachlorobenzene (
HCB). We have studied
heme oxygenase at different times during
HCB treatment and in two strains of rats (Agus and Wistar strains), which are known to differ in their sensitivity to the
porphyria-inducing properties of
HCB, in order to ascertain whether the same time course and genetic differences known to exist for the induction of
porphyria also apply to hepatic oxidative stress.
HCB induced
heme oxygenase and accumulation of
porphyrins in the liver of rats of both strains; no significant difference was found between the two strains in the
HCB-induced
heme oxygenase activity. The increased activity of the
enzyme was first detected during the early phases of treatment, when a modest increase in liver
porphyrins was observed;
heme oxygenase remained at induced levels for several weeks during
HCB treatment, and was still raised when an increase in total liver
iron content and the onset of marked
porphyria were also found. In contrast to the effects of
HCB,
phenobarbitone sodium (given in the
drinking water for up to 4 weeks) produced similar elevations of total liver
cytochrome P450 as
HCB, but did not stimulate
heme oxygenase or increase the total liver content of either
iron or
porphyrins. These results are compatible with an oxidative stress mechanism in
HCB-induced liver toxicity and
porphyria, but also suggest the existence of successive stages in the induction of
hepatic porphyria, with more than one mechanism contributing to the marked accumulation of uroporphyrin.