STIMULATION OF LIVER HEME OXYGENASE IN HEXACHLOROBENZENE-INDUCED HEPATIC PORPHYRIA

We have measured liver heme oxygenase, a heat shock protein known to b e increased under conditions of oxidative stress, to obtain additional evidence for an oxidative stress mechanism in hepatic uroporphyria in duced by hexachlorobenzene (HCB). We have studied heme oxygenase at di fferent times during HCB treatment and in two strains of rats (Agus an d Wistar strains), which are known to differ in their sensitivity to t he porphyria-inducing properties of HCB, in order to ascertain whether the same time course and genetic differences known to exist for the i nduction of porphyria also apply to hepatic oxidative stress. HCB indu ced 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 acti vity of the enzyme was first detected during the early phases of treat ment, when a modest increase in liver porphyrins was observed; heme ox ygenase remained at induced levels for several weeks during HCB treatm ent, 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 fo r up to 4 weeks) produced similar elevations of total liver cytochrome P450 as HCB, but did not stimulate heme oxygenase or increase the tot al liver content of either iron or porphyrins. These results are compa tible 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 cont ributing to the marked accumulation of uroporphyrin.