4-hydroxy-2-nonenal and muconaldehyde

Aldo-keto reductase (AKR) enzymes are critical for the detoxication of endogenous and exogenous aldehydes. Previous studies have shown that the AKR7A2 enzyme is catalytically active toward aldehydes arising from lipid peroxidation, suggesting a potential role against the consequences of oxidative stress, and representing an important detoxication route in mammalian cells. The aim of this study was to determine the ability of AKR7A2 to protect cells against aldehyde cytotoxicity and genotoxicity and elucidate its potential role in providing resistance to oxidative stress. A transgenic mammalian cell model was developed in which AKR7A2 was overexpressed in V79-4 cells and used to evaluate the ability of AKR7A2 to provide resistance against toxic aldehydes. Results show that AKR7A2 provides increased resistance to the cytotoxicity of 4-hydroxynonenal (HNE) and modest resistance to the cytotoxicity of trans, trans-muconaldehyde (MUC) and methyglyoxal, but provided no protection against crotonaldehyde and acrolein. Cells expressing AKR7A2 were also found to be less susceptible to DNA damage, showing a decrease in mutation rate cause by 4-HNE compared to control cells. Furthermore, the role of the AKR7A2 enzyme on the cellular capability to cope with oxidative stress was assessed. V79 cells expressing AKR7A2 were more resistant to the redox-cycler menadione and were able to lower menadione-induced ROS levels in both a time and dose dependent manner. In addition, AKR7A2 was able to maintain intracellular GSH levels in the presence of menadione. Together these findings indicate that AKR7A2 is involved in cellular detoxication pathways and may play a defensive role against oxidative stress in vivo.

Topics: Acrolein; Aldehyde Reductase; Aldehydes; Animals; Caspase 3; Cell Line; Cricetinae; DNA Damage; Glutathione; Humans; Mutagenicity Tests; Oxidative Stress; Pyruvaldehyde; Reactive Oxygen Species

This study investigated the catalytic activities of hepatic glutathione S-transferase (GST) isoenzymes isolated from CD-1 mice toward two activated alkenals of toxicological relevance: trans,trans-muconaldehyde (MA), a putative myelotoxic metabolite of benzene, and trans-4-hydroxy-2-nonenal (HNE), a highly reactive lipid peroxidation product. The activity toward 1-chloro-2,4-dinitrobenzene (CDNB) was also determined. Four isoenzymes with pI values of 9.8, 8.7, 6.4, and 5.7 were each isolated from male and female mice. The isoenzymes with pI values of 8.7 and 6.4 are pi and mu class GSTs, respectively, whereas the pI 9.8 and 5.7 GSTs are both alpha class isoenzymes. CDNB activity was greatest in the pi (pI 8.7) isoenzyme of both sexes. In addition, the CDNB activity of the pi (pI 8.7) isoenzyme from males was markedly greater than the corresponding GST from female mouse liver. In contrast to CDNB, both MA and HNE were better substrates for the acidic alpha (pI 5.7) and mu (pI 6.4) GSTs, whereas minimal activity toward either alkenal was detected in the pi (pI 8.7) and alpha (pI 9.8) isoenzymes. Maximum activity toward MA and HNE was exhibited by the alpha (pI 5.7) isoenzyme of both sexes. The level of HNE activity observed with the alpha (pI 5.7) isoenzyme was five- to sixfold greater than that reported previously for any mouse GST isoenzyme. Moreover, the specific activities of the female alpha (pI 5.7) isoenzyme toward both HNE and MA were markedly greater than those of the corresponding isoenzyme from males. A similar gender-specific difference was noted in the activity of the mu (pI 6.4) isoenzyme toward HNE, but not toward MA. These results show that both MA and HNE are substrates for the alpha (pI 5.7) and mu (pI 6.4) GSTs of murine liver, with maximum activity toward both activated alkenals exhibited by the alpha (pI 5.7) isozyme. In addition, evidence is presented that demonstrates a female-dominant sex difference in the activity of the alpha (pI 5.7) isoenzyme toward MA and HNE, which contrasts sharply with the male-dominant activity of pi class GSTs toward CDNB. These results are consistent with the hypothesis that alpha and mu class GSTs are critical detoxication enzymes in female mouse liver, whereas pi-class GST isozymes predominate in the liver of male mice.

Topics: Aldehydes; Animals; Dinitrochlorobenzene; Female; Glutathione Transferase; Isoenzymes; Liver; Male; Mice; Mice, Inbred Strains; Sex Factors; Substrate Specificity

alpha,beta-Unsaturated aldehydes are reactive compounds which are ubiquitous in the environment. This class of compounds has been tested for mutagenicity in Salmonella typhimurium by a number of groups who have obtained differing results. The present studies were undertaken to test the mutagenicity and toxicity of two novel alpha, beta-unsaturated aldehydes, specifically trans, trans-muconaldehyde and trans-4-hydroxynonenal, and to re-examine the mutagenicity of crotonaldehyde. Trans, trans-muconaldehyde is a newly found microsomal metabolite of benzene, and trans-4-hydroxynonenal is a toxic aldehyde formed endogenously during lipid peroxidation. Compounds were tested in S. typhimurium strain TA 100 using a 30-min liquid preincubation procedure. The present mutagenicity studies indicate that these alpha, beta-unsaturated aldehydes at first appear to be mutagenic, although only at concentrations which decrease survival counts, and result in a disappearance of the bacterial lawn. The colonies observed on mutagenicity test plates are not mutants but rather pin point survivors.

Topics: Aldehydes; Cell Survival; Mutagenicity Tests; Mutagens; Salmonella typhimurium; Structure-Activity Relationship