Superoxide dismutase: the balance between prevention and induction of oxidative damage.
Cu,Zn-superoxide dismutase (SOD1) has been shown to be effective in several free radical mediated diseases, although some studies have pointed toward SOD1 toxicity at a high concentrations. In the present study, the balance between prevention and induction of damage by SOD1 has been investigated both in vitro and in vivo. In vitro superoxide was generated using xanthine/xanthine oxidase. In vivo superoxide was generated using the redox cycling compound doxorubicin. Furthermore, we determined the pharmacokinetics of lecithinized SOD1 (PC-SOD) in order to compare the results obtained in vivo with those obtained in vitro. It was found that in vitro high concentrations of SOD1 induce hydroxylation of coumarin 3-carboxylic acid (3-CCA). This could be caused by a peroxidative action of SOD1 or formation of the highly reactive hydroxyl radicals. Any signs of toxicity are absent in vivo because these concentrations are not reached. It can be concluded that SOD1 possesses a large therapeutic window and application of SOD1 or its derivatives for strengthening the body's defenses against oxidative stress in a variety of pathologies seems safe.
den Hartog
Gertjan J M
GJ
Department of Pharmacology and Toxicology, University Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands. gj.denhartog@farmaco.unimaas.nl
Haenen
Guido R M M
GR
Vegt
Erik
E
van der Vijgh
Wim J F
WJ
Bast
Aalt
A
D000818:Animals; D003374:Coumarins / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D006900:Hydroxylation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000097:blood / Q000378:metabolism*
D003374:Coumarins; D004317:Doxorubicin; D013482:Superoxide Dismutase; C104227:coumarin-3-carboxylic acid