The role of pyrethroid derivatives in autophagy and apoptosis crosstalk signaling and potential risk for malignancies.

Pyrethroids and its derivatives widespread and uncontrolled continuous use has influenced multiple deleterious effects resulting in as a potential risk factor causing damage to the organ systems. Allethrin and prallethrin are extensively used yet their influences on human primary cells are very limited or under reported. The potential mechanisms by which allethrin and prallethrin modulates human primary cells, especially the molecular mechanisms or interconnectivity of autophagy-apoptosis, their clinical relevance in human subjects or patients are not well defined. In this current study, we've furnished the evidence that both allethrin and prallethrin user samples significantly induced Ccl2 mRNA expression, increased amount of reactive oxygen intermediate, inhibited membrane bound enzymes and altered membrane fluidity. Pyrethroid derivative users had induced levels of lipid peroxidation and induced binding activities of transcription factors(tfs) like CEBP-ß and NF-AT. Pyrethroid derivatives induced autophagy, elicited intracellular Ca2+ concentration, calcineurin and regulated proapoptotic genes, DAPK1, Bim. Our current study presumably comprises the initial investigation of a very new mechanism of pyrethroid derivatives-moderated programed cell death in various cell sets or types, like human primary cells where-in this is a late event, is documented. Hence, current research-study might be significant in the various pyrethroid derivatives-allied hematological-related cancers and immunosuppressant or auto-immune disorders. In the foremost instance, we present data stating that pyrethroid derivatives induces multiple cell signaling cascades, like CEBP-ß, NF-AT, ERK and MAPK having a role in autophagy thereby; synchronously effectively impact on the apoptosis, therefore causing hematological tumors and toxic or immune related disorders.

Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin.

Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 µM (OCT1 inhibition by allethrin) to 77.6 µM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 µM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.

Effect of mosquito mats (pyrethroid-based) vapor inhalation on rat brain cytochrome P450s.

The effect of transfluthrin (TF) or D-allethrin (DA) pyrethroid (PYR) vapors, often contained as main ingredients in two commercially available mosquito repellent mats, on cytochrome P450 (CYP) enzymes of rat brain and liver was assessed. Immunodetection of CYP2E1 and CYP3A2 proteins revealed their induction in cerebrum and cerebellum, but not in liver microsomes of rats exposed by inhalation to TF or DA. This overexpression of proteins correlated with an increase of their catalytic activities. The specifically increased expression of CYP isoenzymes, due to PYR exposure in the rat brain, could perturb the normal metabolism of endogenous and xenobiotic compounds and leads to increased risks of neurotoxicity by bioactivation, lipid peroxidation and DNA damage.

Divergent actions of the pyrethroid insecticides S-bioallethrin, tefluthrin, and deltamethrin on rat Na(v)1.6 sodium channels.

We expressed rat Na(v)1.6 sodium channels in combination with the rat beta(1) and beta(2) auxiliary subunits in Xenopus laevis oocytes and evaluated the effects of the pyrethroid insecticides S-bioallethrin, deltamethrin, and tefluthrin on expressed sodium currents using the two-electrode voltage clamp technique. S-Bioallethrin, a type I structure, produced transient modification evident in the induction of rapidly decaying sodium tail currents, weak resting modification (5.7% modification at 100 microM), and no further enhancement of modification upon repetitive activation by high-frequency trains of depolarizing pulses. By contrast deltamethrin, a type II structure, produced sodium tail currents that were ~9-fold more persistent than those caused by S-bioallethrin, barely detectable resting modification (2.5% modification at 100 microM), and 3.7-fold enhancement of modification upon repetitive activation. Tefluthrin, a type I structure with high mammalian toxicity, exhibited properties intermediate between S-bioallethrin and deltamethrin: intermediate tail current decay kinetics, much greater resting modification (14.1% at 100 microM), and 2.8-fold enhancement of resting modification upon repetitive activation. Comparison of concentration-effect data showed that repetitive depolarization increased the potency of tefluthrin approximately 15-fold and that tefluthrin was approximately 10-fold more potent than deltamethrin as a use-dependent modifier of Na(v)1.6 sodium channels. Concentration-effect data from parallel experiments with the rat Na(v)1.2 sodium channel coexpressed with the rat beta(1) and beta(2) subunits in oocytes showed that the Na(v)1.6 isoform was at least 15-fold more sensitive to tefluthrin and deltamethrin than the Na(v)1.2 isoform. These results implicate sodium channels containing the Na(v)1.6 isoform as potential targets for the central neurotoxic effects of pyrethroids.

Profiling the spatial concentration of allethrin and piperonyl butoxide using passive sorptive sampling and thermal desorption capillary GC-MS.

Spatial concentration distribution of a chemical in an indoor environment is an important factor in the evaluation of chemical nuisances. However, straightforward techniques for the determination of this distribution are not very common and usually limited in their application. Sorptive sampling using polydimethylsiloxane-coated stir bars and the combination of active and diffusive sampling were shown to allow uncomplicated spatial concentration profiling of multiple compounds in an indoor environment. The validity of the approach was demonstrated in the analysis of the spatial concentration distribution of a pyrethroid insecticide in a common bedroom. The relative concentrations of allethrin and piperonyl butoxide were profiled throughout the room upon the application of an insecticide vaporizer.

Biodegradation of allethrin, a pyrethroid insecticide, by an acidomonas sp.

Allethrin is a major mosquito repellent agent. To degrade allethrin present in used mats and the environment, a bacterium capable of utilizing allethrin was isolated. This isolate, an Acidomonas sp., grew in minimal medium with 16 mM: allethrin as sole source of carbon and degraded >70% of it in 72 h, with negligible residual metabolites in the medium. Culture filtrates collected after 48 h and 72 h showed presence of (i) cyclopropanecarboxylic acid, 2,2-dimethyl-3-(2-methyl-1-propenyl), (ii) 2-ethyl-1,3-dimethyl-cyclopent-2-ene-carboxylic acid (iii) chrysanthemic acid and (iv) allethrolone [2-cyclopenten-l-one, 4-hydroxy-3-methyl-2(-2-propenyl)] as the major metabolites with 2 minor metabolites. Allethrin is thus metabolized by a hydrolytic pathway followed by oxidation and dehydrogenation.

Liquid chromatography-tandem mass spectrometry for the identification of impurities in d-allethrin samples.

A previous GC/MS study highlighting the impurity profile of the synthetic pesticide d-allethrin is extended here to validate and confirm the impurities identity through the development of soft ionisation HPLC-MS methods. To accomplish this, we developed a reverse phase LC-MS analysis in gradient elution with two distinct soft ionisation techniques, the atmospheric pressure ionisation with electrospray source (API-ESI) and the chemical ionisation (APCI). A single quadrupole and an ion trap, which allowed the simultaneous determination of the molecular masses and structural information of the impurities by acquisition of collisionally induced (CID) product ions spectrum and in-source fragmentation, were employed as analysers. Single quadrupole and ion trap analysers resulted perfectly matching in the d-allethrin impurity fragmentation patterns. All the main impurities over 0.1% identified by GC/MS were confirmed. Results indicate that the proposed HPLC/MS method was found appropriate to confirm the presence of impurities such as chrysolactone, chloro allethrin derivatives, allethrolone and chrysanthemic acid, excluding their formation under GC/MS strong ionisation condition.

QSAR studies of the pyrethroid insecticides. Part 3. A putative pharmacophore derived using methodology based on molecular dynamics and hierarchical cluster analysis.

Previous studies of the conformational behaviour of a group of synthetic pyrethroid insecticides have been extended to a more structurally diverse set. This includes compounds with different backbones and differing stereochemistry, with both Types I and II biological activity. These compounds also encompass a large range of biological activities. A parameterisation of the CHARMM force field for these compounds has been performed and the extra parameters are reported. Conformational sampling, using molecular dynamics (MD), has been performed for each of the 41 active structures. The accessible conformations of each have been characterised by the values of the common torsion angles using hierarchichal cluster analysis (HCA). A further CA, based on the centroids derived from the conformational sampling, identified a conformation common to at least 39 of the 41 structures. The critical torsion angles of this conformation lie at the centre of the molecule about the ester linkage and are defining an extended conformation, which differs from the minimum energy conformation of deltamethrin used previously. This may represent a putative pharmacophore for kill. The methods used here improve significantly on those used previously. The CHARMM force field was parameterised for the compounds and an improved method of conformational sampling, based on centroid clustering, has also been used.

[Determination of optical purity of SR-bioallethrin enantiomers by chiral high performance liquid chromatography].

A chiral stationary phase(CSP) was prepared by coating cellulose-tris (3,5-dimethylphenylcarbamate) onto aminopropylated spherical silica gel. On the CSP, the chiral separation of the bioallethrin enantiomers has been investigated and under the optimum conditions the optical purity of three samples of SR-bioallethrin enantiomers was determined by peak area. The results show that the method established is very ideal for determining the optical purity and evaluating the quality of the samples.

Management of endemic outbreaks of scabies with allethrin, permethrin, and ivermectin.

BACKGROUND: At three residences for the elderly, recurrent scabies infestations became out of control. Due to the failure of repeated, nonsynchronized therapeutic efforts with conventional external anti-scabies treatments, an eradication program had to be developed. We describe a protocol for the management of outbreaks of scabies. METHODS: According to the clinical examination and microscopically identified mites, all individuals of the population (IOP: patients, staff, and family members) were divided into two groups: (a) healthy and infested IOP; and (b) cases with crusted scabies. The first group was treated simultaneously once with external scabicides (allethrin or permethrin). All others were hospitalized and treated either with systemic ivermectin or with the latter in combination with permethrin. RESULTS: In 252 IOP living in three residences for the elderly, clinical signs of scabies were reported in 91.5%, 78.5%, and 15.4% of the patients (age 55-97 years; mean, 80.5 years), 54.1%, 32.9%, and 16.6% of staff members, and in 7%, 3%, and 0% of family members. The infested IOP showed crusted scabies (index cases) in 5.3%, 5.0%, and 1.7%, common scabies in 43.1%, 36.7%, and 7.1%, and postscabiotic dermatitis in 10.3%, 7.6%, and 3.5%. In 99.2% of the synchronously treated IOP in group (a) (n = 240), the conventional treatment with permethrin cream 5% or allethrin spray was effective. Group (b) (n=12) received ivermectin (12 mg) once (n=5) or twice (n= 7) after an interval of 8 days. One index case received permethrin three times. CONCLUSIONS: Outbreaks of scabies in populations of elderly people require special management for disease control. Synchronous treatment with external permethrin cream 5% or allethrin spray, including all IOP once, and close control offers a time-saving, cheap, and reliable method. Crusted scabies should be treated by oral administration of ivermectin once or twice after an interval of 8 days. Additional applications of permethrin and mechanical clearing of hyperkeratotic subungual areas shorten the course.

Carbon-based quantitation of pyrethrins by supercritical-fluid chromatography.

All six insecticide active ingredients in pyrethrum extract were quantified by supercritical fluid chromatography and carbon calibration. Allethrin is a suitable reference compound for carbon calibration and pyrethrins calibrations. Carbon quantification in SFC is also applied to pyrethroids (phenothrin, permethrin, cypermethrin, fenvalerate and deltamethrin) and alkanes. Halogen substitution on pyrethroids requires halogens on the reference calibration compound. The method was applied to commercial extracts.

Bioefficacy of mosquito mat, coil and dispenser formulations containing allethrin group of synthetic pyrethroids against mosquito vectors.

The bioefficacy of mats, coils and dispensers containing allethrin group of synthetic pyrethroids was studied against laboratory strains of Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi. Except esbiothrin in the mat formulation which was 100 and 178 times more effective against Cx. quinquefasciatus than against Ae. aegypti and An. stephensi with KT50 of 0.005, 0.5 and 0.89 min. respectively, all the three allethrins in mat or coil formulations were equally effective against the three vector mosquitoes. When compared to mat formulations of d-allethrin and bioallethrin, mat formulation of esbiothrin was 156 and 144 times more effective against Cx. quinquefasciatus. It was 162 times more effective against Cx. quinquefasciatus than in the coil formulation. Dispenser containing d-allethrin was the least effective against Cx. quinquefasciatus (KT50: 2.65 min.) and Ae. aegypti (KT50: 4.68 min.) but as effective as coil against An. stephensi. When mat and dispenser heated or coil burnt continuously for 10 hours the knockdown was consistently above 60% in all the three vector species but mortality was not consistently > 60% in Ae. aegypti. Repellent effect of the formulations ranged from 0.0 to 80.3%, 0 to 57.3% and 59.2 to 78.3% against Cx. quinquefasciatus Ae. aegypti and An. stephensi respectively. Repellency was more against An. stephensi than against the other two species. Mats and coils deterred > 50% of the mosquitoes from feeding on the chicken (range: 50 to 99.52%) but in case of dispenser the effect was only 14.72 to 65.01%. The use of these formulations as a control tools in reducing man-vector contact is discussed.

Effect of the pyrethroid insecticide allethrin on membrane fluidity.

Allethrin is a widely used pyrethroid insecticide with an alkenylmethylcyclopentenolone group in its structure. We have analyzed its interaction with model and native membranes using DPH and its polar derivative TMA-DPH fluorescence polarization. Allethrin modified the bilayer order in the temperature range of the phase transition when incorporated into liposomes made with dimyristoyl-(DMPC), dipalmitoyl-(DPPC) and distearoyl-(DSPC) phosphatidylcholine. In DMPC: allethrin mixtures the pyrethroid decreased the bilayer order in the gel phase, without altering the liquid-crystalline one. In native membranes, DPH and TMA-DPH fluorescence polarization remained unchanged after incubation with allethrin. The release of hemoglobin was notably facilitated by the incorporation of allethrin into human erythrocytes. The results are discussed in terms of a possible aggregation of the insecticide in the lipid bilayer to create special domains with a consequent increase in membrane instability.