PON1 increases cellular DNA damage by lactone substrates.

PON1 increases cellular DNA damage by lactone substrates.
Arch Toxicol. 2019 Jun 17;:
Authors: Shangula S, Noori M, Ahmad I, Margison GP, Liu Y, Siahmansur T, Soran H, Povey AC
Abstract
Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme that by hydrolysing exogenous and endogenous substrates can provide protection against substrate induced toxicity. To investigate the extent to which PON1 provides protection against lactone induced DNA damage, DNA damage was measured in HepG2 cells using the neutral Comet assay following lactone treatment in the presence and absence of exogenous recombinant PON1 (rPON1). Low dose lactones (10 mM) caused little or no damage while high doses (100 mM) induced DNA damage in the following order of potency: α-angelica lactone > γ-butyrolactone ~ γ-hexalactone > γ-heptalactone ~ γ-octaclactone ~ γ-furanone ~ γ-valerolactone > γ-decalactone. Co-incubation of 100 mM lactone with rPON1, resulted in almost all cells showing extensive DNA damage, particularly with those lactones that decreased rPON1 activity by > 25%. In contrast, with the lactones that are poor rPON1 subtrates (γ-decalactone and γ-furanone), rPON1 did not increase DNA damage. DNA damage induced by a 1 h co-treatment with 10 mM α-angelica lactone and rPON1 was reduced when cells when incubated for a further 4 h in fresh medium suggesting break formation was due t...

Source: Archives of Toxicology - June 16, 2019 Category: Toxicology Authors: Shangula S, Noori M, Ahmad I, Margison GP, Liu Y, Siahmansur T, Soran H, Povey AC Tags: Arch Toxicol Source Type: research