Protoporphyrin IX and oxidative stress

Abstract

The short- and long-term pro-oxidant effect of protoporphyrin IX (PROTO) administration to mice was studied in liver. A peak of liver porphyrin accumulation was found 2 h after the injection of PROTO (3.5 mg/kg, i.p.); then the amount of porphyrins diminished due to biliar excretion. After several doses 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 synthetase was induced 70-90% over the control values 4 h after the first injection of PROTO and stayed at these high levels throughout the period of the assay. Administration of PROTO induced rapid liver damage, involving lipid peroxidation. Hepatic GSH content was increased 2h after the first injection of PROTO, but then decreased below the control values which were maintained 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 peroxidase (GPx), while decreased GSH levels induced glutathione reductase (GRed) activity. However after 5 doses of PROTO, the activity of SOD was reduced reaching control values. GPx and catalase activities slowly went down, while GRed continued increasing as long as the levels of GSH were kept very low. TBARS values, although lower than those observed after a single dose of 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 oxidative 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 is compromised.

Action of protoporphyrin-IX (PP-IX) in the lifespan of <i>Drosophila melanogaster</i> deficient in endogenous antioxidants, Sod and Cat

“…Another example that supports this hypothesis is that PP-IX has been used for several years in photodynamic therapy [14,[44][45][46]. This is so due to its ability to induce superoxide radicals that react with molecular oxygen producing peroxide radicals which cause lipid peroxidetion, and leading to different cell damages such as structural changes of the cell membrane, damage to proteins, inactivation of receptors, enzymes and ion channels, all of which can lead to cell death [47].…”

“…Some studies have provided evidence that the PP-IX can act as either pro-oxidant or antioxidant; for example, in the presence of light, PP-IX stimulates lipid peroxidation by Fe +2 and ascorbate [13] whereas lipid peroxidation is inhibited in darkness. Increased levels of Sod were also found in mice treated with PP-IX, suggesting that it induces the formation of superoxide radicals [14]. In rat strain CF1, Sod was rapidly induced after a single dose of PP-IX suggesting that superoxide radicals had been generated [14].…”

“…Increased levels of Sod were also found in mice treated with PP-IX, suggesting that it induces the formation of superoxide radicals [14]. In rat strain CF1, Sod was rapidly induced after a single dose of PP-IX suggesting that superoxide radicals had been generated [14].…”

“…likely that under those conditions PP-IX produces no action on the superoxide generated by the radiation, but probably acts as a pro-oxidant generating superoxide as demonstrated by Afonso et al [14].…”

“…However, as mentioned earlier this compound, as well as PP-IX are capable of inducing genetic damage probably through generation of ROS [10,14]. To evaluate this possibility, and based on the fact that increased ROS levels accelerate the aging process, we defined our aim in this research as the assessment of the role of PP-IX in the lifespan of D. melanogaster strains deficient in CuZnSod and Cat.…”