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  • Title: Self-sensitized photodegradation of membrane-bound protoporphyrin mediated by chain lipid peroxidation: inhibition by nitric oxide with sustained singlet oxygen damage.
    Author: Niziolek M, Korytowski W, Girotti AW.
    Journal: Photochem Photobiol; 2005; 81(2):299-305. PubMed ID: 15647001.
    Abstract:
    In the presence of exciting light, iron and reductants, the singlet oxygen (1O2)-generating sensitizer protoporphyrin IX (PpIX) induces free radical lipid peroxidation in membranes, but gradually degrades in the process. We postulated that NO, acting as a chain-breaking antioxidant, would protect PpIX against degradation and consequently prolong its ability to produce 1O2. This idea was tested by irradiating PpIX-containing liposomes (LUVs) in the presence of iron and ascorbate, and monitoring the cholesterol hydroperoxides 5alpha-OOH and 7alpha/beta-OOH as respective 1O2 and free radical reporters. 5alpha-OOH accumulation, initially linear with light fluence, slowed progressively after prolonged irradiation, whereas 7alpha/beta-OOH accumulation only accelerated after an initial lag. The active, but not spent, NO donor spermine NONOate (0.4 mM) virtually abolished 7alpha/beta-OOH buildup as well as 5alpha-OOH slowdown. Increasing membrane phospholipid unsaturation hastened the onset of rapid chain peroxidation and 5alpha-OOH slowdown. Accompanying the 5alpha-OOH effect was a steady decrease in 1O2 quantum yield and PpIX fluorescence at 632 nm, both of which were inhibited by NO. An NO-inhibitable decay of PpIX fluorescence was also observed during dark incubation of 5alpha-OOH-bearing LUVs with iron and ascorbate, confirming a link between chain peroxidation and PpIX loss. By protecting PpIX in irradiated membranes, NO might select for and prolong purely 1O2-mediated damage. Supporting this was our observation that 1O2-mediated photoinactivation of a nonmembrane target, lactate dehydrogenase, slowed concurrently with 5alpha-OOH accumulation and that spermine NONOate prevented this. Thus, NO not only protected membrane lipids against PpIX-sensitized free radical damage, but PpIX itself, thereby extending its 1O2-generating lifetime. Consistent findings were obtained using porphyrin-sensitized COH-BR1 cells. These previously unrecognized effects of NO could have important bearing on 5-aminolevulinate-based photodynamic therapy in which PpIX is metabolically deposited in tumor cells.
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