Disease relevance of Regent

• Mechanisms for selective toxicity of fipronil insecticide and its sulfone metabolite and desulfinyl photoproduct [1].
• Fipronil modulation of gamma-aminobutyric acid(A) receptors in rat dorsal root ganglion neurons [2].
• Phenylpyrazole insecticide fipronil induces male infertility in the estuarine meiobenthic crustacean Amphiascus tenuiremis [3].
• Consistent with the hypothesis that notochord degeneration may be due to abnormal mechanical stress from muscle tetany, the expression patterns of gene and protein markers specific to notochord development were unaffected by fipronil [4].
• Effect of topical application of fipronil in cats with flea allergic dermatitis [5].

Psychiatry related information on Regent

• Laboratory studies of Melanoplus sanguinipes demonstrated that fipronil was horizontally transferred at lethal levels (p < 0.05) via cannibalism through four passages when the initial dose applied to a food source was 250 times the label rate for rangeland grasshopper and locust control (label rate is 4 g AI/ha) [6].

High impact information on Regent

• The persistence of this photoproduct and its high neuroactivity, resulting from blocking the lambda-aminobutyric acid-gated chloride channel, suggest that it may be a significant contributor to the effectiveness of fipronil [7].
• RDL is the target of the commercially important insecticide fipronil [8].
• Of the four receptor variants tested, the double mutant showed the highest resistance to fipronil, following repeated GABA applications [9].
• In conclusion, although fipronil sulfone is a potent inhibitor of cockroach GABA receptors, desensitizing and nondesensitizing GluCls, and rat GABA(A) receptors, its selective toxicity in insects over mammals appears to be associated with its potent blocking action on both desensitizing and nondesensitizing GluCls, which are lacking in mammals [10].
• After repetitive activation of the receptors, the IC50 of fipronil sulfone to block the desensitizing GluCls was reduced from 350 to 25 nM and that for blocking nondesensitizing GluCls was reduced from 31.2 to 8.8 nM [10].

Chemical compound and disease context of Regent

• To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique [11].
• In this study, we examine the mechanisms for selective toxicity of the sulfoxide fipronil and its sulfone metabolite and desulfinyl photoproduct relative to their target site interactions in vitro and ex vivo and the importance in fipronil action of biooxidation to the sulfone [1].
• Specificity between mammals and insects at the target site (fipronil > lindane > alpha-endosulfan) paralleled that for toxicity [12].
• Although specifically developed to target insect GABA receptors with low vertebrate toxicity, our results suggest that fipronil impairs the development of spinal locomotor pathways in fish by inhibiting a structurally related glycine receptor subtype [4].
• On days 0, 30, 60, 90, and 120, dogs (12/group) were treated by topical administration of selamectin (6 mg/kg [2.7 mg/lb] of body weight), fipronil (7.5 mg/kg [3.4 mg/lb]), or imidacloprid (10 mg/kg [4.5 mg/lb]); 8 untreated dogs were used as controls [13].

Biological context of Regent

• Resistance to fipronil in Drosophila simulans: influence of two point mutations in the RDL GABA receptor subunit [9].
• Ex vivo inhibition of [3H]EBOB binding in mouse brain is similar for fipronil and its sulfone and desulfinyl derivatives at the LD50 dose, but surprisingly, at higher doses fipronil can be lethal without detectably blocking the [3H]EBOB site [1].
• Fipronil is the first phenylpyrazole insecticide introduced for pest control [2].
• Experiments with coapplication of fipronil and picrotoxinin indicated that they did not compete for the same binding site to block the receptor [2].
• 3. Mutant RDL GABA-receptors, which have a naturally occurring amino acid substitution (A302-->S) in the putative ion-channel lining region, conferring resistance to dieldrin and picrotoxinin, were markedly less sensitive to fipronil than the wild-type receptors [14].

Anatomical context of Regent

• In order to assess the individual and combined roles of the two mutations in fipronil resistance, the functional properties of wild-type, A301G, T350M and A301G/T350M homomultimeric RDL receptors were compared by expression in Xenopus oocytes [9].
• Single channel analysis of the blocking actions of BIDN and fipronil on a Drosophila melanogaster GABA receptor (RDL) stably expressed in a Drosophila cell line [15].
• The notochord effects of fipronil were phenocopied by exposure to 70 microM strychnine, a glycinergic receptor antagonist [4].
• Fish rapidly accumulated all compounds, as measured in the carcass (whole body minus liver and GI tract) during the 32 d uptake phase, which was followed by varying elimination rates of the chemicals (half-lives (t1/2s) ranging from 0.6 d for fipronil to 77.0 d for PCB 174) during the 96 d depuration period [16].
• The results indicate both that HepG2 cells and primary human hepatocytes are sensitive to the cytotoxic effects of fipronil [17].

Associations of Regent with other chemical compounds

• GLC-3: a novel fipronil and BIDN-sensitive, but picrotoxinin-insensitive, L-glutamate-gated chloride channel subunit from Caenorhabditis elegans [18].
• Several pathways were available for fipronil photodegradation in this system, including direct photolysis and indirect photooxidation by species produced during the illumination of natural waters (e.g., 3NOM*, 1O2*, *OH, *CO3(1-), *OOR, *OOH, e(aq)-, O2(*-)) [19].
• Evaluation of efficacy of selamectin, fipronil, and imidacloprid against Ctenocephalides felis in dogs [13].
• First, from published data, alpha-endosulfan, lindane and fipronil compete for the [(3)H]EBOB binding site with affinities of 0.3--7 nM in both human recombinant homooligomeric beta 3 receptors and housefly head membranes [20].
• These findings suggest that horizontal and trophic transfer probably play a nominal ecotoxicological role in rangeland grasshopper control programs with diflubenzuron, but the transfer of fipronil to grasshoppers, scavengers, and natural enemies via necrophagy may increase both the efficacy of control programs and their environmental affects [6].

Gene context of Regent

• Exposure of human hepatocytes to doses of fipronil (5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl) sulfinyl]-1H-pyrazole-3-carbonitrile) ranging from 0.1 to 25muM resulted in a dose dependent increase in CYP1A1 mRNA expression (3.5 to approximately 55-fold) as measured by the branched DNA assay [17].
• Metabolic sulfone formation is more rapid with ethiprole than fipronil in human expressed CYP3A4 in vitro and mouse brain and liver in vivo [21].
• CYP3A4 is the major isoform responsible for fipronil oxidation in humans while CYP2C19 is considerably less active [22].
• Fipronil sulfone was the predominant metabolite via CYP oxidation [22].
• Stage-I juvenile copepods were individually reared to adults in aqueous microvolumes of the phenylpyrazole insecticide, fipronil, and whole-body homogenate extracts were assayed for VTN levels [23].

Analytical, diagnostic and therapeutic context of Regent

• [(3)H]Ethynylbicycloorthobenzoate ([(3)H]EBOB), a high affinity radioligand for the noncompetitive blocker site of the GABA(A) receptor, is used here for quantitative autoradiography to determine regional binding in mouse brain and the effects on this binding of administering toxic doses of endosulfan, fipronil, and avermectin B(1a) (AVM) [24].
• Standard toxicological bioassays using fipronil aqueous solutions from 1 to 2000 nM indicated different sensitivity levels among species [25].
• The adulticidal activity of fipronil was determined by flea comb counts 48h after treatment and then 48h after each reinfestation [26].
• On days 0, 30, 60, 90, and 120, sixteen cats (8 pairs/treatment group) were treated by topical administration of selamectin (6 mg/kg [2.7 mg/lb] of body weight) or fipronil (7.5 mg/kg [3.4 mg/lb]) [27].
• The recoveries of fipronil by this ELISA were in the range of 80-120% [28].

References