Biological effects of menadione photochemistry: effects of menadione on biological systems may not involve classical oxidant production

Abstract

Because cell-mediated reduction of menadione leads to the generation of reactive oxygen species (ROS), this quinone is widely used to investigate the effects of ROS on cellular functions. We report that A549 human lung epithelial cells exposed to menadione demonstrate a dose-dependent increase in both intracellular calcium ([Ca(2+)](i)) and ROS formation. The concentrations of menadione required to initiate these two events are markedly different, with ROS detection requiring higher levels of menadione. Modulators of antioxidant defences (e.g. buthionine sulphoximine, 3-amino-1,2,4-triazole) have little effect on the [Ca(2+)](i) response to menadione, suggesting that ROS formation does not account for menadione-dependent alterations in [Ca(2+)](i). Additional evidence suggests that menadione photochemistry may be responsible for the observed [Ca(2+)](i) effects. Specifically: (a) EPR studies with the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) show that light exposure (maximum effect at 340 nm) stimulates menadione-dependent formation of the DMPO/(.)OH spin adduct that was not sensitive to antioxidant interventions; (b) DMPO inhibits menadione and light-dependent increases in [Ca(2+)](i); and (c) light (maximum effect at 340 nm) augments the deleterious effects of menadione on cell viability as determined by (51)Cr release. These photo effects do not appear to involve formation of singlet oxygen by menadione, but rather are the result of the oxidizing chemistry initiated by menadione in the triplet state. This work demonstrates that menadione species generated by photo-irradiation can exert biological effects on cellular functions and points to the potential importance of photochemistry in studies of menadione-mediated cell damage.

Circadian rhythms in Neurospora crassa: Downstream effectors

“…The rhythm in L/L with menadione apparently does not require the frq gene, the vvd gene, or the wc-1 or wc-2 genes. The fact that light effects were seen in the null mutants could be due to the fact that menadione has been reported (McCormick et al, 2000) to be involved in photo-chemical reactions. The rhythm in L/L is quantitatively affected by the csp-1 mutation, but not the csp-2 mutation.…”

“…Parallel studies on the effects of the sod-1 mutants, which should affect ROS levels, have also shown evidence of effects on banding and period (Yoshida et al, 2008). Menadione may also be involved in photo-chemical reactions (McCormick et al, 2000) which could explain, in part, the data shown in Fig. 4.…”

From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements

“…The photosensitized generation of reactive oxygen species, e.g. from hydroperoxides, may account for susceptibility of the triplet oxygen (peroxidase) pathway to illumination [57]. The hydroperoxide 11, under the conditions of its formation from 10, is converted into the enol 12.…”

Inhibition of apoptosis by menadione on exposure to UVA

“…McCormick et al (2000) reported that menadione was more toxic in the presence of UV irradiation (365 nm) and the increase in toxicity arose from photochemical products of the interaction of light with menadione rather than an increase in the production of ROS. Almost all studies reported that the toxicity due to the photosensitization of menadione is caused by a type I reaction, which produces no ROS and changes the photoirradiated compound into radicals, and suggested that the biological effects of menadione's photosensitization were due to the modification of DNA bases by one-electron oxidation (Douki and Cadet, 1999;.…”