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The role of pyridine nucleotides in quinone-induced cell death

Morgan, Winston Antonio; (1993) The role of pyridine nucleotides in quinone-induced cell death. Doctoral thesis (Ph.D.), University College London (United Kingdom). Green open access

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Abstract

The depletion of the pyridine nucleotide NAD^ observed during oxidative stress has often been attributed to hydrolysis. However recently an interconversion of NAD(H) to NADP(H) was proposed. Using rat hepatocytes, the changes in pyridine nucleotides induced by several redox cycling quinones as well as the organic hydroperoxide tert-butyl hydroperoxide (tBH) were investigated. The exposure of rat hepatocytes to redox cycling quinones such as 2^-dimethoxy- 1,4-naphthoquinone (2,3-diOMe-l,4-NQ) or to tBH resulted in a rapid depletion of N AD\ The depletion of NAD^ was accompanied by an increase in nicotinamide. In hepatocytes preincubated for one hour with inhibitors of poly(ADP-ribose)polymerase then exposed to either 23-diOMe-l,4-NQ or tBH, the rate of NAD^ depletion was significantly reduced. 2,3-diOMe-l,4-NQ induced extensive oxidation of NADPH which was followed by an increase in level of NADP^ + NADPH. The increase in NADP^ + NADPH was equivalent to the decrease in NAD^ and no change in the total pyridine nucleotide { NAD(H) + NADP(H) } level was observed. In hepatocytes exposed to tBH, the oxidation of NADPH was not accompanied by an increase in the level of NADP"^ + NADPH and a decrease in total pyridine nucleotides was observed. These observations suggest that during oxidative stress, the depletion of NAD"^ results from the activation of poly(ADP-ribose)polymerase which hydrolyses NAD^ to nicotinamide and that the depletion of NAD^ is independent of the increase in NADP(H). The activation of poly(ADP-ribose)polymerase and the depletion of NAD"^ are often associated with DNA damage. In human myeloid leukaemic cells (K562), both 23-diOMe-l,4-NQ and menadione induced DNA strand breaks at very early time points (< 5 min). The strand breaks induced by both quinones were inhibited by the iron chelator 1,10-phenanthroline. Where strand breaks are rapidly repaired, cell proliferation is unaffected. Conversely at concentrations which cause extensive strand breakage less strand scission repair is observed and the rate of cell proliferation is significantly inhibited. These results suggest that a brief exposure to low concentrations of some redox cycling quinones results in a delayed cell death, preceded by DNA damage and the depletion of NAD\

Type: Thesis (Doctoral)
Qualification: Ph.D.
Title: The role of pyridine nucleotides in quinone-induced cell death
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: (UMI)AAIU057089; Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10109661
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