Paraoxonase-1, an organophosphate detoxifier and cardioprotective enzyme, is inhibited by anesthetics: An in vitro and in vivo insight

Paraoxonase-1 enzyme (PON1) is important in metabolism as an organophosphate (OP) hydrolyser, hydrolyses aromatic carboxyl esters, such as phenyl acetate, and is involved in drug and xenobiotic metabolism. Moreover, it hydrolyses various lactones, including naturally occurring lactone metabolites. PON1 also acts as an antioxidant bio-scavenger and protects low-density lipoproteins (LDL) from oxidative modifications. As PON1 levels are influenced by many environmental factors and this might be dangerous, interactions between these factors and HDL-associated enzyme PON1 should be well characterized. The objective of this study was to evaluate the in vitro and in vivo effects of the intravenous anesthetics, midazolam, diazepam, tramadol, pethidine and lidocaine, on the activity of human and rabbit serum paraoxonase-1. PON1 was purified from human serum with a final specific activity of 5685.7 U mg(-1) and a purity of 37.74% using simple chromatographic methods. The five anesthetics dose-dependently decreased in vitro hPON1 activity, with IC50 values for midazolam, diazepam, tramadol, pethidine and lidocaine of 0.085, 0.104, 0.282, 0.463 and 1.678 mM, respectively. K-i constants were 0.057, 0.181, 0.317, 0.632 and 1.174 mM, respectively. Anesthetics showed two different inhibition mechanisms: midazolam, diazepam and tramadol was noncompetitive, others were competitive. In vivo studies were performed on five male New Zealand White rabbits for each drug. Rabbit serum PON1 activity was significantly inhibited by 0.2 mg/kg midazolam, 2 mg/kg diazepam, 2 mg/kg lidocaine, 5 mg/kg tramadol and 5 mg/kg pethidin for up to 30 min following intravenous administration. Our results showed that anesthetics significantly inhibit hPON1 activity, both in vitro and in vivo, with rank order midazolam > diazepam > tramadol > pethidine > lidocaine in vitro; and lidocaine > pethidin > tramadol > midazolam > diazepam in vivo. (C) 2011 Elsevier Inc. All rights reserved.