The Molecular Effects of Acrolein

Abstract

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in a variety of environmental situations, particularly as a component of smoke. In addition, as a metabolite of cyclophosphamide, acrolein is a major factor in the toxicity and perhaps the therapeutic activity of this important anticancer agent. The exposures to acrolein that are attained in vivo in most situations are quite low and the effects may differ from those seen at acutely toxic doses. At low doses, acrolein inhibits cell proliferation without causing cell death and may enhance apoptosis from secondary toxins, while at higher doses oncosis ensues. Although the acute toxicology of acrolein has been extensively investigated, both in animals and cultured cells, little information exists on the molecular effects of this reactive aldehyde. It is possible that the acrolein-mediated decrease in cell proliferation is caused by effecting changes in the expression of one or more growth- or stress-related genes or transcription factors secondary to a reduction in glutathione (GSH), which is rapidly depleted following acrolein treatment. It is apparent that the activation of the transcription factors nuclear factor kappa B (NF-kappa B) and activator protein 1 (AP-1) can be inhibited by acrolein. The purpose of this review is to assess the literature currently available on the molecular effects of acrolein, to discuss the relationship between effects on glutathione with those on various genes, and to present some new data showing that acrolein actively stimulates genes associated with the electrophile response element.

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

“…Acrolein-induced toxicity has previously been reviewed by Beauchamp et al [92] and by Kehrer and Biswal [93]. Numerous studies indicate that acrolein-induced toxic effects can at least to some extent be rationalized by depletion of cellular GSH [93].…”

“…Numerous studies indicate that acrolein-induced toxic effects can at least to some extent be rationalized by depletion of cellular GSH [93]. In addition, acrolein exerts its biological effects through reaction with nucleophilic sites in proteins, i.e., the sulfhydryl group of cysteine, the imidazole moiety of histidine, and the ε-amino group of lysine, thereby impairing protein function.…”

Acrolein induces selective protein carbonylation in synaptosomes

“…As a consequence, the identification of acrolein adducts has been proposed as a biologic marker for oxidative stress (Kehrer and Biswal, 2000). Accordingly, acrolein levels have been found increased in pathological conditions associated with oxidative stress, such as spinal cord injury (Luo et al, 2005), diabetic nephropathy (Suzuki and Miyata, 1999) and Alzheimer's Disease (AD) (Markesbery and Lovell, 1998,Calingasan et al, 1999,Lovell et al, 2001).…”

Neuron differentiation and neuritogenesis stimulated by N-acetylcysteine (NAC)

“…Oxidative stress, which can lead to various disorders, is thought to be caused by two kinds of compounds: 1) ROS, such as superoxide anion radical O 2 ·-, hydrogen peroxide (H 2 O 2 ) and hydroxyl radical (·OH), and 2) unsaturated aldehydes, such as acrolein and hydroxynonenal [32,33] . There are many reports concerning the roles of ROS and unsaturated aldehydes in cell damage, and it is thought that ROS play a predominant role in cell damage.…”