Protoporphyrin IX and oxidative stress

The short- and long-term pro-oxidant effect of protoporphyrin IX (PROTO) ad ministration to mice was studied in liver. A peak of liver porphyrin accumu lation was found 2 h after the injection of PROTO (3.5 mg/kg, i.p.); then t he amount of porphyrins diminished due to biliar excretion. After several d oses of PROTO (1 dose every 24 h up to 5 doses) a sustained enhancement of liver porphyrins was observed. The activity of delta-aminolevulinic acid sy nthetase was induced 70-90% over the control values 4 h after the first inj ection of PROTO and stayed at these high levels throughout the period of th e assay. Administration of PROTO induced rapid liver damage, involving lipi d peroxidation. Hepatic GSH content was increased 2 h after the first injec tion of PROTO, but then decreased below the control values which were maint ained after several doses of porphyrin. After a single dose of PROTO, Cu-Zn superoxide dismutase (SOD) was rapidly induced, suggesting that superoxide radicals had been generated. Increased levels of hydrogen peroxide coming from the reaction catalyzed by SOD and lipid peroxides as a consequence of membrane peroxidation, induced the activity of catalase and glutathione per oxidase (GPx), while decreased GSH levels induced glutathione reductase (GR ed) activity. However after 5 doses of PROTO, the activity of SOD was reduc ed reaching control values. GPx and catalase activities slowly went dawn, w hile GRed continued increasing as long as the levels of GSH were kept very low. TEARS values, although lower than those observed after a single dose o f PROTO, remained above control values; Glutathione S-transferase activity was instead greatly diminished, indicating sustained liver damage. Our findings would indicate that accumulation of PROTO in liver induces oxi dative stress, leading to rapid increase in the activity of the antioxidant enzymes to avoid or revert liver damage. However, constant accumulation of porphyrins provokes a liver damage so severe that the antioxidant system i s compromised.