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Cellular toxicity of quinones: Redox- and addition chemistry
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
1992 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1992. , 81 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 362
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-28095Local ID: 12861ISBN: 91-7870-905-9OAI: diva2:248646
Public defence
1992-05-22, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-07-19Bibliographically approved

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