Perturbation of Rat Heart Plasma Membrane Fluidity Due to Metabolites of Permethrin Insecticide

Abstract

Due to increased global use, acute and chronic exposures to pyrethroid insecticides in humans are of clinical concern. Pyrethroids have a primary mode of action that involves interference with the sodium and calcium channels in excitable cells, which may include cardiac myocytes. Here, we investigated the possible cardiac toxicity of permethrin metabolites (METP), 3-phenoxy-benzyl alcohol (3PBA), 3-phenoxy-benzaldehyde (3PBALD), and 3-phenoxybenzoic acid (3PBACID). Plasma membrane fluidity, polarity, lipid, and protein oxidation were studied in isolated rat heart cells. Laurdan was chosen as probe to detect the lateral mobility and polarity of its environment and thus water penetration into the hydrophobic part of the bilayer, while 1,6-diphenyl-1,3,5-hexatriene permits to measure changes in fluidity in the inner part of the bilayer. Results show that METP can change membrane fluidity at different depths of the bilayer according to their partition coefficient. Consequently, 3PBA, at all concentration used, decreases membrane fluidity and polarity in the hydrophilic-hydrophobic region of the bilayer, and similar effect was observed with 20 μM 3PBALD or 10 or 20 μM 3 PBACID. Membrane dynamics in the hydrophobic core resulted decreased by 3PBALD, while it was increased by 20 μM 3PBACID. All METP increase protein and lipid oxidation, and the peroxidative lipid damage decreases with the type of METP produced during the transformation pathway from parent compound to 3PBACID. Consequently, 3PBA induced the highest lipid peroxidation, while 3PBACID was the stronger inducer of protein damage.

Exercise‐induced heart mitochondrial cholesterol depletion influences the inhibition of mitochondrial swelling

“…The varied response of mitochondria associated with changes in the cholesterol pool during stress circumstances has been observed. As has been recently reported, the mitochondrial cholesterol content of rat hearts is reduced during oxidative stress (Vadhana et al 2011 a ). Lower cholesterol levels in these mitochondria have been associated with DNA damage, increased protein carbonyl content and lipid hydroperoxide formation in cardiac cells.…”

“…Remodelling of mitochondrial cholesterol content has been noted in physiological conditions and in vitro . A significant reduction in the cholesterol content of cardiac mitochondria has been observed in rats treated with permethrin, an oxidative stress‐inducing agent (Vadhana et al 2011 a ). It has been also shown that prolonged swimming decreases the cholesterol content of cardiac mitochondria (Keatisuwan et al 1991).…”

“…Preparation of heart cells The hearts were collected, rinsed with ice‐cold PBS, and the ventricles were dissected into small fragments using a surgical blade (Vadhana et al 2010, 2011 a , b ). The samples were then homogenized in a glass tube with a pestle and extensively washed again in cold PBS until blood cells were not observed and then minced using 0.9% NaCl.…”

A novel role of Drosophila cytochrome P450-4e3 in permethrin insecticide tolerance

“…Which mechanisms contribute to the deleterious effects on survival observed in the Cyp4e3 knockdown flies on PM diet? Previous studies have shown an increase in ROS production upon PM exposure ( Hu et al., 2010 , Vadhana et al., 2011 ). To determine if the oxidative effects induced by the insecticide metabolism is recapitulated in wild-type flies fed with PM, we measured tubule H 2 O 2 levels.…”

“…Recent studies have shown increased reactive oxygen species (ROS) production upon permethrin (PM) exposure in rat adrenal pheochromocytoma cells or cardiac myocytes ( Hu et al., 2010 , Vadhana et al., 2011 ). Thus, we examined if the oxidative effects induced by PM metabolism are recapitulated in an organotypic context, the Malpighian (renal) tubule, an important epithelial tissue for xenobiotic handling.…”