nontoxic concentrations of menadione

Oxidative stress is thought to be a mechanism of many forms of liver injury. Although reactive oxygen species (ROS) may directly damage cellular macromolecules, oxidant-induced cell death may result from redox effects on signal transduction pathways. To understand the mechanism of oxidative stress-induced hepatocyte death, the function of menadione in mitogen-activated protein kinase (MAPK) during oxidant-induced hepatocyte injury was determined. Low, nontoxic, and highly toxic concentrations of the superoxide generator menadione were established in the RALA255-10G rat liver cell line. Menadione-induced death was blocked by catalase and ebselen, suggesting that death was secondary to oxidant generation rather than arylation. Treatment with nontoxic concentrations of menadione resulted in transient activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In contrast, treatment with toxic concentrations of menadione induced prolonged activation of ERK and JNK. Chemical inhibition of ERK function kills RALA hepatocytes at previously nontoxic concentrations of menadione and is associated with sustained JNK activation. Adenoviral expression of a dominant negative protein of c-Jun, a downstream substrate of JNK, prevents menadione-induced death. The pro-apoptotic effect of c-Jun is not mediated through the mitochondrial death pathway. In conclusion, resistance of RALA hepatocytes to menadione oxidant-induced death is ERK-dependent, and cell death is mediated by AP-1 activation. These findings identify signaling pathways that may be therapeutic targets for preventing or treating oxidant-induced liver injury
Menadione-catalyzed production of H2O2 by viable cells is proportional to the number of viable cells, this assay for H2O2 production was applied to the cytotoxicity test of 17 substances used in the international validation of the fixed-dose procedure as a classical LD (50 ) test. The cytotoxicity of the test substances was observed after 4 hours of incubation with the animal cells and the viability was determined within 10 minutes according to the menadione-catalyzed H2O2 production assay. The IC(50) of each substance required for 50% inhibition of menadione-catalyzed H2O2 production was similar in HepG2, HuH-6KK, HUVE, Vero, Intestine 407, NIH/3T3 and Neuro-2a cells. The LD(50) and IC(50) of 12 substances, 3 substances and 2 substances exhibited differences of 1, 2 and 3 orders of magnitude, respectively. These results suggest that the menadione-catalyzed H2O2 production assay is useful for the rapid detection of toxic compounds with basal cytotoxicity shared by various cells, but not suitable for the detection of organ-specific toxic compounds [208].
It is well documented that menadione-induced oxidative stress can lead to elevated intracellular Ca2+ in various tissues. Increased Ca2+ levels in platelets lead to platelet aggregation. To test the hypothesis that menadione-induced Ca2+ elevation plays a role in platelet aggregation, we investigated the effect of menadione on the aggregation of platelets isolated from female rats. Treatment of PRP with menadione (which has been shown to be an adequate system) appears to induce dose-dependent turbidity changes in platelets of up to 60%

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