Pyridine nucleotide changes in hepatocytes exposed to quinones.
Quinones may be toxic by a number of mechanisms, including arylation and oxidative stress caused by redox cycling. Using isolated hepatocytes, we have studied the cytotoxicity of four quinones, with differing abilities to arylate cellular nucleophiles and redox cycle, in relation to their effects on cellular pyridine nucleotides. High concentrations of menadione (redox cycles and arylates), 2-hydroxy-1,4-naphthoquinone (neither arylates nor redox cycles via a one electron reduction) 2,3-dimethoxy-1,4-naphthoquinone (a pure redox cycler) and p-benzoquinone (a pure arylator) caused an initial decrease in NAD+ and loss of viability, which was not prevented by 3-aminobenzamide, an inhibitor of poly(ADP-ribose)polymerase. In contrast, 3-aminobenzamide inhibited the loss of NAD+ and viability caused by dimethyl sulphate so implicating poly(ADP-ribose)polymerase in its toxicity but not that of the quinones. Non-toxic concentrations of menadione, 2,3-dimethoxy-1,4-naphthoquinone and 2-hydroxy-1,4-naphthoquinone all caused markedly similar changes in cellular pyridine nucleotides. An initial decrease in NAD+ was accompanied by a small, transient increase in NADP+ and followed by a larger, prolonged increase in NADPH and total NADP+ + NADPH. Nucleotide changes were not observed with non-toxic concentrations of p-benzoquinone. Our findings suggest that a primary event in the response of the cell to redox cycling quinones is to bring about an interconversion of pyridine nucleotides, in an attempt to combat the effects of oxidative stress.
Cohen
G M
GM
Department of Pharmacology, School of Pharmacy, University of London, UK.
Stubberfield
C R
CR
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000633:toxicity; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009243:NAD / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D010084:Oxidation-Reduction; D011809:Quinones / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D001549:Benzamides; D011809:Quinones; D009243:NAD; D009249:NADP; C025160:3-aminobenzamide; D004121:Dimethyl Sulfoxide