Acrolein inactivates paraoxonase 1: changes in free acrolein levels after hemodialysis correlate with increases in paraoxonase 1 activity in chronic renal failure patients.

摘要

BACKGROUND: Acrolein is a very reactive aldehyde present in cigarette smoke and endogenously generated by pathways such as lipid peroxidation and threonine metabolism by phagocytes. Acrolein has been shown to affect uptake of cholesterol by HDL. We hypothesized that acrolein could also have deleterious effects on paraoxonase 1 (PON-1) activity. We also determined whether free serum acrolein levels are higher in renal failure, and assessed whether they decrease after hemodialysis (HD) and whether this change correlates with increases in PON-1 activity. METHODS: We incubated human HDL with 0-10 mmol/l acrolein for 2 h and measured PON-1 activity and structural changes. Acrolein was also measured in 40 end stage renal disease (ESRD) patients (before and after a hemodialysis session), and 40 control subjects. RESULTS: We found that acrolein inhibits PON-1 activity in HDL in a time and concentration dependent fashion. Inhibition occurred at 40% at 0.5 mmol/l and was cancelled by cysteine but not by aminoguanidine or carnosine. We confirm that free serum acrolein levels are higher in chronic renal failure patients and demonstrate that they are partially removed by HD. Decrease in acrolein levels after dialysis correlate with increases in PON-1 activity (r=0.32, p 0.01). CONCLUSION: Acrolein inactivates paraoxonase 1 in HDL, a process that is inhibited by N-acetylcysteine. We confirm that acrolein levels are higher in ESRD and show for the first time, data supporting that acrolein is partially removed by hemodialysis. Decrease in acrolein levels after dialysis correlates with increase in PON-1 activity. This could offer new insights to explain low PON-1 activities in smokers and renal failure subjects as well as pointing at thiol-conserving reducing compounds such as N-acetylcysteine, as putative therapeutic palliatives.