Afonso S, Vanore G, Batlle A
Centro de Investigaciones sobre Porfirinas y Porfirias, CONICET, School of Sciences, University of Buenos Aires, Argentina.
Free Radic Res. 1999 Sep;31(3):161-70. doi: 10.1080/10715769900300711.
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.
研究了向小鼠腹腔注射原卟啉IX（PROTO，3.5mg/kg）后在肝脏中的短期和长期促氧化作用。注射PROTO后2小时发现肝脏卟啉积累达到峰值；随后由于胆汁排泄，卟啉量减少。在多次注射PROTO（每24小时1次，共5次）后，观察到肝脏卟啉持续增加。首次注射PROTO后4小时，δ-氨基乙酰丙酸合成酶的活性比对照值诱导增加70-90%，并在整个测定期间保持在这些高水平。注射PROTO会引起快速的肝脏损伤，包括脂质过氧化。首次注射PROTO后2小时肝脏谷胱甘肽（GSH）含量增加，但随后降至对照值以下，而在多次注射卟啉后对照值保持不变。单次注射PROTO后，铜锌超氧化物歧化酶（SOD）迅速被诱导，表明已产生超氧自由基。由SOD催化的反应产生的过氧化氢水平升高以及膜过氧化导致的脂质过氧化物增加，诱导了过氧化氢酶和谷胱甘肽过氧化物酶（GPx）的活性，而GSH水平降低则诱导了谷胱甘肽还原酶（GRed）的活性。然而，在注射5次PROTO后，SOD的活性降低至对照值。GPx和过氧化氢酶的活性缓慢下降，而只要GSH水平保持在非常低的水平，GRed就持续增加。硫代巴比妥酸反应物（TBARS）值虽然低于单次注射PROTO后观察到的值，但仍高于对照值；相反，谷胱甘肽S-转移酶活性大大降低，表明存在持续的肝脏损伤。我们的研究结果表明，PROTO在肝脏中的积累会诱导氧化应激，导致抗氧化酶活性迅速增加以避免或逆转肝脏损伤。然而，卟啉的持续积累会引发严重的肝脏损伤，以至于抗氧化系统受到损害。
