Molecular mechanisms of acrolein-mediated cytotoxicity

Acrolein is chemical that is ubiquitously present in low concentrations in our environment, while in high concentration in cigarette smoke. Its underlying mode of toxicity, apoptosis vs. oncosis/ necrosis, is however unclear. Apoptosis is the preferred pathway because it results in cell death that does not affect surrounding cells or tissue. To date, high doses of acrolein have demonstrated only modest levels of apoptosis. We show that in B lymphocytic cells acrolein induces primarily oncotic/ necrotic cell death rather than apoptosis. The choice of death pathways may be due to acrolein’s inhibition of ATP, which is required for apoptotic processes to properly function. It may also be due to acrolein’s inhibition of caspases-3, -8, and –9, which are three main proteolytic enzymes involved in mediating an apoptotic response. Acrolein’s electrophilic nature may be involved in the inhibition of caspases, which have a cysteine residue in their catalytic domain, as well as do numerous other proteins involved in maintaining a cell’s redox status. Glutathione (GSH) is an important element of the cellular redox and electrophile defense system. However, its broad-based actions make it difficult to discern what cellular components are being affected by alterations in GSH levels. In a parallel redox pathway, thioredoxin (Trx) plays a vital role in regulating multiple transcription factors including NF-kB and AP-1 (via Redox factor-1). Due to their importance in maintaining cell homeostasis, alterations in the activities of NF-kB and AP-1 greatly affects cellular functioning. The current data demonstrate an acrolein-induced loss of immunoreactive Trx protein and activity concomitantly with decreased GSH. Formation of antisense Trx cells demonstrated that Trx loss is involved in decreasing the DNA binding and recovery of NF-kB and AP-1 following acrolein treatment. Overall, acrolein induces a primarily oncotic/ necrotic form of cell death, potentially mediated by it inhibition of caspases and ATP loss. At non-lethal doses, it clearly affects cysteine-containing molecules, GSH, Trx, NF-kB, and AP-1, thus acknowledging the importance of acrolein’s strong electrophilic nature. The key regulator of acrolein-mediated stress is unclear, although its effect on these factors likely alters normal cell functioning.Pharmac