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Sökning: L4X0:0345 0082 > (1990-1994) > (1992)

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  • Öllinger, Karin, 1962- (författare)
  • Cellular toxicity of quinones : Redox- and addition chemistry
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Quinoid compounds are widely occurring in nature. They have cytotoxic properties and they are also used as antineoplastic agents. The cytotoxic properties can be explained by the ability of quinones to generate active oxygen species by redox cycling, by addition to cellular nucleophiles, and by inhibition of DNA transcription.This study aims to the characterisation of free radical generating capacity and electrophilicity of 1,4- naphthoquinones as a function of their substitution pattern. Further, the mechanism for adriamycin toxicity to heart myocytes has been investigated.The two-electron reducing enzyme DT-diaphorase reduces 1,4-naphthoquinones bearing methyl-, hydroxy-, methoxy-, and glutathionyl substituents to their corresponding 1 ,4-naphthohydroquinone. The 1 ,4-naphthohydroquinones bearing hydroxy- and glutathionyl substituents are readily oxidized by oxygen, generating superoxide anion radicals and subsequently hydrogen peroxide. All quinones studied can be reduced by the one-electron reducing enzyme NADPH cytochrome P-450 reductase yielding semiquinones that efficiently reduces oxygen to superoxide anion radicals.The nucleophilic addition of glutathione to un- and benzene-ring hydroxy substituted 1,4- naphthoquinones proceeds with glutathione addition at rates decreasing with the number of hydroxy groups, reflecting the decreased electrophilicity of these quinones.The effect of hydroxy-substituent position on 1 ,4-naphthoquinone toxicity in primary rat hepatocyte cultues revealed that substituents in the benzene ring increase the toxicity, compared to 1 Anaphthoquinone, due to an increased efficiency ofredoxcycling. Hydroxy-substituent in the quinoid ring renders a quinone that is much less cytotoxic due to decreased electrophilicity and unfavorable reduction potential.The antineoplastic drug Adriamycin has the broadest spectrum of activity of all chemotherapeutic agents. Its clinical use, however, is diminished by an unique cardiamyopathy. The involvment of oxygen free radicals in adriamycin cardiotoxicity was investigated using primary cultured neonatalrat heart myocytes. The toxicity decreased at low oxygen pressure and was further decreased by addition of the antioxidant N,N' -diphenyl-p-phenylenediamine, indicating that generation of free radicals contribute to the myocardial toxicity.
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  • Resultat 31-31 av 31
  • Föregående 123[4]
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