Moreover, our findings suggest that mitochondrial thioredoxin oxidation and glutathionylation may contribute to the initiation of toxicity.
The third aim sought to identify oxidation-sensitive proteins that are affected by APAP-induced oxidative stress in vivo.
We found evidence of oxidative stress occurring soon after exposure to APAP and affecting the oxidation status of peroxiredoxin, a redox system that ultimately depends on functional Trx R and thioredoxin for regeneration.
Peroxiredoxin over-oxidation combined with an observed loss of thioredoxin disulfide reducing activity is suggestive of a significant role for the thioredoxin system in propagating APAP-induced oxidative stress and toxicity.
Abstract: The first aim of this dissertation was to investigate the effects of APAP-induced electrophilic stress on the two major redox nodes, thioredoxin and glutathione.
Experiments were designed to monitor changes to either node following hepatotoxic doses of APAP in comparison to known indicators of oxidative stress and liver injury.
Importantly, these findings were not observed with AMAP or its metabolism to reactive intermediates, suggesting a selective mechanistic link between electrophilic stress and downstream signaling triggered by some molecules such as APAP in drug-induced toxicity.
The second aim sought to characterize the effects of APAP-induced stress on redox signaling proteins that are dependent on maintenance of the thioredoxin system's redox equilibrium.