Stimulation of liver heme oxygenase in hexachlorobenzene-induced hepatic porphyria.
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.
Stonard
M D
MD
Central Toxicology Laboratory, Zeneca, Macclesfield, Cheshire, UK.
Poli
G
G
De Matteis
F
F
D000818:Animals; D004790:Enzyme Induction; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000187:drug effects*; D006581:Hexachlorobenzene / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects*; D017094:Porphyrias, Hepatic / Q000139:chemically induced / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D014578:Uroporphyrins / Q000378:metabolism
D014578:Uroporphyrins; D006581:Hexachlorobenzene; D006419:Heme Oxygenase (Decyclizing)