Phenylpyrazole Insecticide Photochemistry, Metabolism, and GABAergic Action:  Ethiprole Compared with Fipronil

Abstract

Ethiprole differs from fipronil, the major phenylpyrazole insecticide, only in an ethylsulfinyl substituent replacing the trifluoromethylsulfinyl moiety. This study compares their photochemistry, metabolism, action at the gamma-aminobutyric acid (GABA) receptor, and insecticidal potency. On exposure to sunlight as a thin film, ethiprole undergoes oxidation (major), reduction, and desethylsulfinylation but not desulfinylation whereas the major photoreaction for fipronil is desulfinylation. Metabolic sulfone formation is more rapid with ethiprole than fipronil in human expressed CYP3A4 in vitro and mouse brain and liver in vivo. High biological activity is observed for the sulfide, sulfoxide, sulfone, and desulfinyl derivatives in both the ethiprole and the fipronil series in GABA receptor assays (human recombinant beta3 homomer and house fly head membranes) with [(3)H]EBOB and in topical toxicity to house flies with and without the P450-inhibiting synergist piperonyl butoxide. On an overall basis, the ethiprole series is very similar in potency to the fipronil series.

Sulfone Metabolite of Fipronil Blocks γ-Aminobutyric Acid- and Glutamate-Activated Chloride Channels in Mammalian and Insect Neurons

“…The metabolite was also found in the brain and liver of mice treated i.p. with fipronil (Caboni et al, 2003). In European corn borer (Ostrinia nubilalis Hubner), fipronil sulfone was formed through the microsomal cytochrome P450 oxidation system in the midgut in vivo and in vitro (Durham et al, 2002).…”

“…In European corn borer (Ostrinia nubilalis Hubner), fipronil sulfone was formed through the microsomal cytochrome P450 oxidation system in the midgut in vivo and in vitro (Durham et al, 2002). The biological conversion of fipronil to fipronil sulfone was completely blocked with piperonyl butoxide, a cytochrome P450 monooxygenase inhibitor, in vivo and in vitro (Hainzl et al, 1998;Caboni et al, 2003). This inhibitor has been used in vivo to test whether or not the metabolites of fipronil are active as insecticides.…”

Use of non-mammalian alternative models for neurotoxicological study

“…The biological conversion of fipronil to fipronil sulfone was blocked by piperonyl butoxide (Hainzl et al, 1998;Caboni et al, 2003). However, it was unlear whether the conversion of fipronil to its sulfone represented detoxication in mammals and insects.…”

Citotoxicity of Fipronil on Hepatocytes Isolated from Rat and Effects of Its Biotransformation

“…Once in the blood, fipronil and its metabolites are widely distributed, particularly in adipose tissues, and have a high level of enterohepatic recirculation (Hainzl and Casida 1996;Mohamed et al 2004). The formation of the sulfone metabolite, which is derived from an oxidation reaction of the thioether group, corresponds to the primary route of hepatic metabolism of the compound (Caboni et al 2003;Tang et al 2004). According to Leghait et al (2009), this oxidation is catalyzed by cytochrome P450 coenzymes, principally CYP3A4.…”