| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2580676 | Chemico-Biological Interactions | 2012 | 8 Pages |
A β-lapachone analogue (3,4-dihydro-2,2-dimethyl-9-chloro-2H-naphtho[1,2b]pyran-5,6-dione) (9-chloro β-lapachone), named CGQ, with antitumoral, antiviral and antitrypanocidal activities was assayed for cytotoxic effects on isolated rat hepatocytes. The incubation of hepatocytes with this o-naphthoquinone showed (a) decreased adenylate energy charge, as a result of a decrease in ATP, and an increase in AMP levels; (b) increased NADP+ content, with a concomitant decrease of NADPH, NADH and NAD+ content; (c) decreased GSH content, accompanied by an increase in GSSG formation; (d) stimulated oxygen uptake as well as increased superoxide anion production and hydrogen peroxide formation; (e) inhibited lipid peroxidation; (f) hepatocyte viability was not reduced unless the NQO1 inhibitor dicoumarol was present. We hypothesize that the cytotoxicity of CGQ in dicoumarol-treated hepatocytes was the result of inhibition of the NQO1 detoxification pathway, thus allowing more quinone to be metabolized towards the one-electron pathway to form reactive semiquinones and/or reactive oxygen species. The results obtained indicate a protective role of NQO1 in preventing CGQ cytotoxicity in isolated rat hepatocytes.
Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We examined 9-chloro-β-lapachone(CGQ) for cytotoxicity in isolated hepatocytes. ► Changes in ATP and AMP levels were not sufficient for induction of cell death. ► We report redox-cycling by CGQ in isolated hepatocytes. ► Hepatocyte viability was not reduced by CGQ unless DT-diaphorase was inhibited. ► We suggest a protective role of DT-diaphorase in preventing CGQ cytotoxicity.
