Effect of hydroxy substituent on the prooxidant action of naphthoquinone compounds
Introduction
Naphthoquinone compounds, widely distributed in plants have pharmacological and toxicological importance, and are often used as cancer chemotherapeutic drugs, antimalarials, antibacterial agents and fungicides (O’Brien, 1991, Monks et al., 1992). Cytotoxic action of naphthoquinones varies depending on the structure of the compounds: juglone, 5-hydroxy-1,4-naphthoquinone causes cell death of some types of cells, whereas lawsone, 2-hydroxy-1,4-napthoquinone shows little or no cytotoxicity (Kumbhar et al., 1996) (Fig. 1). These cytotoxic effects have been explained by the decrease in glutathione due to the enzymatic redox cycling of naphthoquinones (Ross et al., 1986, Öllinger and Brunmark, 1991), and by the formation of adducts to DNA and protein (Rossi et al., 1986). In the present work, we analyzed the direct prooxidant action of naphthoquinone compounds with a focus on the lipid peroxidation, and the formation of DNA base adduct, 8-hydroxy-2′-deoxyguanosine. Prooxidant properties of naphthoquinones were closely related to the enhancement of autooxidation of reduced iron. Juglone with the electron-repelling hydroxyl group in the benzene moiety was suggested to form semiquinone radical causing potent oxidative damage of DNA and lipids, whereas naphthoquinones with hydroxyl group in the quinone moiety showed a weak cytotoxicity that was ascribed to the reduction of transition metals forming oxygen radicals.
Section snippets
Materials
Juglone, plumbagin, shikonin, menadione, lawsone, lapachol, DMPO (5,5′-dimethyl-1-pyrroline N-oxide), 8-hydroxy-2′-deoxyguanosine, enzymes for DNA hydrolysis, and bathophenanthroline disulfonate were obtained from Sigma–Aldrich Chemicals (Tokyo, Japan). NADP-Isocitrate dehydrogenase is a product of Oriental Yeast Co. (Osaka, Japan). Other chemicals were obtained from commercial sources.
Lipid peroxidation of liver microsomes
Microsomes were prepared from the livers of adult male rats by standard differential centrifugation techniques
Effect of napththoquinone compounds on the microsomal lipid peroxidation
We examined the effect of naphthoquinone compounds (Fig. 1) on the lipid peroxidation of microsomes from rat liver (Fig. 2). Naphthoquinone compounds with 5-hydroxyl group enhanced lipid peroxidation. Juglone and shikonin of lower concentration markedly increased the thiobarbituric acid-reactive substances as a marker of lipid peroxidation, but these compounds of higher concentrations rather tended to decrease the formation of thiobarbituric acid-reactive substances. Plumbagin at its higher
Discussion
Quinones are widely distributed in nature and play an essential biological role in mitochondrial respiration and photosynthesis. Some quinone compounds such as benzoquinone and naphthoquinones show potent cytotoxic and anti-proliferative effects on various cells and organisms (Öllinger and Brunmark, 1991, Kumbhar et al., 1996, Inbaraj and Chignell, 2004), and have been used for topical treatment of certain diseases (O’Brien, 1991, Monks et al., 1992). Quinone toxicity has been studied
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