PON1 increases cellular DNA damage by lactone substrates.

Area of Science:

• Biochemistry
• Toxicology
• Molecular Biology

Background:

• Paraoxonase 1 (PON1) is an HDL-associated enzyme known for hydrolyzing various substrates.
• PON1 typically offers protection against substrate-induced toxicity.
• The role of PON1 in modulating lactone-induced DNA damage is not fully understood.

Purpose of the Study:

• To investigate the effect of recombinant PON1 (rPON1) on lactone-induced DNA damage in HepG2 cells.
• To determine if PON1 can protect against or exacerbate lactone-induced genotoxicity.

Main Methods:

• HepG2 cells were treated with various lactones at different concentrations (10 mM and 100 mM).
• DNA damage was assessed using the neutral Comet assay.
• Cells were co-incubated with or without exogenous recombinant PON1 (rPON1) and pre-incubated with rPON1 and lactones.

Main Results:

• High doses (100 mM) of certain lactones induced significant DNA damage, with α-angelica lactone being the most potent.
• Co-incubation with rPON1 at 100 mM lactone concentrations generally increased DNA damage, especially for lactones that decreased rPON1 activity.
• Pre-incubation of α-angelica lactone with rPON1 reduced subsequent cellular DNA damage, suggesting PON1 hydrolysis products may be genotoxic.

Conclusions:

• PON1 can unexpectedly enhance lactone-induced genotoxicity, potentially by hydrolyzing lactones into reactive intermediates that form DNA adducts.
• These findings suggest a dual role for PON1, where its detoxification capacity can be context-dependent.
• Further research is needed to elucidate the specific mechanisms of PON1-mediated genotoxicity.