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Cited by 34Neuroscience and Neuropharmacology ResearchPesticide Exposure and ToxicityNicotinic Acetylcholine Receptors Study

The insecticide fipronil and its metabolite fipronil sulphone inhibit the rat α1β2γ2L GABAAreceptor

Open access
Li, P, Akk, G·2008·British Journal of Pharmacology
DOI 10.1038/bjp.2008.309PMC PMC2584928
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Abstract

Human exposure to fipronil leads to symptoms (headache, nausea and seizures) typically associated with the antagonism of GABA A receptors in the brain. In this study, we have examined the modulation of the common brain GABA A receptor subtype by fipronil and its major metabolite, fipronil sulphone. Whole-cell and single-channel recordings were made from HEK 293 cells transiently expressing rat alpha1beta2gamma2L GABA A receptors.

Integrity signals

Registry

Crossref · 10.1038/bjp.2008.309

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

2 of 31 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Human exposure to fipronil leads to symptoms (headache, nausea and seizures) typically associated with antagonism of GABA_A receptors in the brain.

    “Human exposure to fipronil leads to symptoms (headache, nausea and seizures) typically associated with the antagonism of GABA A receptors in the brain.”
    • Also stated in: § Introduction · plain
      “This results in symptoms and complications typically associated with the blockade of the GABA A receptor function, for example, headache, nausea and seizures (Mohamed et al., 2004).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mohamed et al., 2004 source

      The Discussion’s “Clinical features of acute human toxicity” section reports nausea and seizures in patients with fipronil poisoning, while “Mechanism of toxicity” says fipronil inhibits GABA-gated chloride channels and binds to GABA_A receptors. The paper does not report headache among the human symptoms, so that part of the attributed symptom list is unsupported. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Subunit composition differences affect both kinetics and pharmacology of the GABA_A receptor.

    “Subunit composition differences are known to affect both kinetics and pharmacology of the GABA A receptor (see Ebert et al., 1997;Picton and Fisher, 2007)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Ebert et al., 1997 source

      The indexed copy lists several GABA_A receptor α subunits and ligand-affinity data, which supports the pharmacology portion of the claim. It provides no passage showing that subunit composition affects receptor kinetics; the only mention of “Rate Constant” is a generic database heading. The available passages have no section or page labels. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
    • cites Picton and Fisher, 2007 source
  • Findingown data

    The α1V256S mutation has a relatively small effect on channel block by fipronil.

    “The a1V256S mutation, previously shown alleviate channel inhibition by inhibitory steroids and several insecticides, had a relatively small effect on channel block by fipronil.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Fipronil sulphone is less potent than fipronil at inhibiting the α1β2γ2L GABA_A receptor.

    “but the metabolite was less potent at inhibiting the a1b2g2L receptor.”
    • Also stated in: § Introduction · plain
      “the metabolite was 10-fold less effective in producing channel inhibition.”
    Quote in the paperSubstantial claim
  • Findingown data

    Fipronil shortens single-channel cluster durations of α1β2γ2L GABA_A receptors.

    “In single-channel recordings, the presence of fipronil resulted in shorter cluster durations without affecting the intracluster open and closed time distributions or the single-channel conductance.”
    • Also stated in: § The presence of fipronil affects single-channel cluster durations but not intracluster open and closed time distributions · plain
      “The inclusion of fipronil in the pipette medium resulted in shorter clusters.”
    Quote in the paperSubstantial claim
  • May combine two claims. 23
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingown data

    Fipronil and fipronil sulphone inhibit the rat α1β2γ2L GABA_A receptor.

    “We found that fipronil and fipronil sulphone inhibit the receptor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The time constant for reduction of peak current as a function of preincubation duration is 19±4 s, saturating at 43±3% of control.

    “The relationship between the fractional peak current and preincubation duration (Figure 4b) was fitted with a single exponential yielding a time constant of 19±4 s saturating at 43±3% of control.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upon removal of fipronil, recovery proceeded with a time constant of 5.3 s to a maximal current level of 77 pA, similar to the steady-state level in the control GABA response from the same cell (92 pA).

    “Upon the removal of fipronil from the bath solution, recovery proceeded with a time constant of 5.3 s to a maximal current level of 77 pA.This is similar to the steady-state level in the control GABA response from the same cell (92 pA).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The kon and koff values for unliganded receptors are 5 times and 77 times slower, respectively, than the respective rates in the presence of 1 mM GABA.

    “These values are 5 times and 77 times, respectively, slower than the respective rates in the presence of 1 mM GABA.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    The chord conductance at −100 mV in inside-out patches is 24.7 ± 1.1 pS (n=4 patches) in the presence of 1 mM GABA and 26.1±0.9 pS (n=4 patches) in the presence of 1 mM GABA + 20 mM fipronil.

    “The single-channel conductance was 24.7 ± 1.1 pS (n ¼ 4 patches) in the presence of 1 mM GABA and 26.1± 0.9 pS (n ¼ 4 patches) in the presence of 1 mM GABA þ 20 mM fipronil.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    For unliganded receptors, koff is 0.023 s−1 and kon is 0.003 mM−1 s−1 (3×10^3 M−1 s−1).

    “From these values, we postulate (10 mM k on þ k off ) ¼ 1/19 s and k off /(10 mM k on þ k off ) ¼ 0.43, yielding a k off of 0.023 s À1 and a k on of 0.003 mM À1 s À1 (3 Â 10 3 M À1 s À1 ).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: In the simplest model, the current decay rate in the presence of 1 mM GABA + 10 mM fipronil consists of the sum of the desensitization rate estimated in the absence of fipronil and the rate of fipronil-induced inhibition.

  • May combine two claims.

    Findingown data

    Fipronil acts by speeding the decay rate in macroscopic recordings and reducing the mean cluster duration in single-channel recordings.

    “The experiments described above demonstrate that fipronil acts by speeding the decay rate in macroscopic recordings and reducing the mean cluster duration in single-channel recordings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For GABA + 10 mM fipronil, kon is 0.22 mM−1 s−1, similar to the macroscopic estimate (0.23 mM−1 s−1).

    “For GABA þ 10 mM fipronil, we calculate k on ¼ (2.5À0.3 s À1 )/10 mM ¼ 0.22 mM À1 s À1 .This value is gratifyingly similar to the k on estimate obtained in macroscopic recordings (0.23 mM À1 s À1 ).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: In the simplest model, the current decay rate in the presence of 1 mM GABA + 10 mM fipronil consists of the sum of the desensitization rate estimated in the absence of fipronil and the rate of fipronil-induced inhibition.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The time course of current desensitization in the presence of GABA was dominated by a single exponential.

    “In agreement with previous data (Benkwitz et al., 2004), we found that the time course of current desensitization in the presence of GABA was dominated by a single exponential.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Benkwitz et al., 2004 source

  • May combine two claims.

    Findingown data

    The concentration-effect relationship for the decay time constant yields an IC50 of 1.1±0.2 mM and a Hill slope of 1.3±0.2.

    “The curve was fitted to the Hill equation yielding an IC 50 of 1.1±0.2mM and a Hill slope of 1.3 ± 0.2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A 2-s application of 1 mM GABA plus 10 mM fipronil fully inhibited the response, leading to a steady-state current level equal to 2.6% of the peak response.

    “a 2-s application of GABA þ 10 mM fipronil fully inhibited the response leading to the steadystate current level that equalled 2.6% of the peak response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Receptor affinity, channel gating properties and single-channel conductance are not affected in the presence of fipronil.

    “Receptor affinity, channel gating properties and single-channel conductance are not affected in the presence of the drug.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mode of action of fipronil sulphone was similar to fipronil, but fipronil sulphone was a weaker antagonist of the receptor than fipronil.

    “The mode of action of fipronil sulphone was similar, but fipronil sulphone was a weaker antagonist of the receptor than fipronil.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Fipronil slowly and reversibly inhibits GABA_A receptors.

    “Similar to that study, we found that fipronil slowly and reversibly inhibits GABA A receptors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ikeda et al., 2001 source

  • May combine two claims.

    Findingown data

    Fipronil did not affect the affinity of the receptor to GABA, the channel gating properties, or the conductance of the ion channel.

    “Fipronil did not affect the affinity of the receptor to GABA, the channel gating properties, or the conductance of the ion channel.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The k_on was 0.23 mM^-1 s^-1 in α1β2γ2L receptors and more than 30-fold less (0.007 mM^-1 s^-1) in native receptors in DRG.

    “The k on was 0.23 mM À1 s À1 in a1b2g2L receptors and more than 30-fold less (0.007 mM À1 s À1 ) in native receptors in DRG.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Our data indicate that fipronil does not modulate agonist binding or channel opening; instead, its presence leads to early termination of single-channel clusters.

    “Our data, on the basis of singlechannel cluster analysis, indicate that fipronil does not modulate agonist binding or channel opening, instead, its presence leads to early termination of single-channel clusters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Fipronil's mode of action in insects is through inhibition of glutamate- and GABA-activated chloride channels, resulting in uncontrolled neural excitation and death.

    “Fipronil's mode of action is through the inhibition of glutamate-and GABA-activated chloride channels resulting in uncontrolled neural excitation and, eventually, the death of the insect (see Narahashi et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Narahashi et al., 2007 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fipronil is a negative allosteric modulator of the GABA_A receptor in DRG neurons.

    “it was concluded that fipronil is a negative allosteric modulator of the GABA A receptor in DRG neurons (Ikeda et al., 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ikeda et al., 2001 source

  • May combine two claims.

    Premisecitation

    Both unliganded closed and open channels can interact with fipronil, although channel activation appears to enhance the association and dissociation rates for the drug.

    “Both unliganded closed and open channels can interact with fipronil, although channel activation appears to enhance the association and dissociation rates for the drug (Ikeda et al., 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ikeda et al., 2001 source

  • May combine two claims.

    Interpretationown data

    Fipronil-induced inhibition proceeds in parallel with and independently of channel desensitization.

    “This process proceeds in parallel with and independently of, channel desensitization.”
    • Also stated in: § Does fipronil promote channel desensitization? · hedged
      “We interpret the results to indicate that the receptors inhibited by fipronil are capable of desensitizing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fipronil sulphone is more potent (by almost an order of magnitude) than fipronil in blocking GABA_A receptor currents in rat DRG neurons.

    “In contrast, Zhao et al. (2005) found that fipronil sulphone is more potent (by almost an order of magnitude) than fipronil in blocking GABA A receptor currents in rat DRG neurons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhao et al., 2005 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The presence of the FLAG tag in the α1-subunit is without effect on the kinetics of macroscopic currents or GABA dose-response properties.

    “The presence of the FLAG tag in the a-subunit is without effect on the kinetics of macroscopic currents or GABA dose-response properties (Ueno et al., 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ueno et al., 1996 source

  • May combine two claims.

    Study design and conductcitation

    In whole-cell recordings, the presence of the γ-subunit in the receptor complexes was verified from the position of the GABA dose-response curve, which is significantly left-shifted for αβ-containing receptors compared to αβγ receptors.

    “In whole-cell recordings, the presence of the g-subunit in the receptor complexes was verified from the position of the GABA dose-response curve, which is significantly left-shifted for the ab-containing receptors compared to the abg receptors (Boileau et al., 2003;P Li and G Akk, unpublished data).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Boileau et al., 2003 source
    • cites P Li and G Akk, unpublished data

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In both mammals and insects, fipronil is rapidly converted to fipronil sulphone.

    “In both mammals and insects, fipronil is rapidly converted to fipronil sulphone (Figure 1b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hainzl et al., 1998 source

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    The findings could also be accounted for by a mechanism in which fipronil inhibits the receptor by promoting entry into a distinct, long-lived nonconducting (blocked) state.

    “However, the findings could also be accounted for by a mechanism in which fipronil inhibits the receptor by promoting entry into a distinct, long-lived nonconducting, that is, blocked state.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The molecular mechanism by which fipronil acts on GABA_A receptors in the brain remains largely unknown.

    “Despite such strong incentives, the molecular mechanism by which fipronil acts on GABA A receptors in the brain remains largely unknown.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Fipronil does not affect the receptor affinity to GABA or the channel-opening rate constant.

    “Accordingly, we conclude that fipronil does not affect the receptor affinity to GABA or the channel-opening rate constant.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    For the recovery peak to be observed, recovery from fipronil inhibition must proceed rapidly compared with the development of desensitization.

    “We note a caveat, that recovery from the inhibition must proceed rapidly compared with the development of desensitization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Our data on recovery from block are consistent with a model where fipronil-induced inhibition and channel desensitization proceed in parallel and independently, indicating that fipronil induces the accumulation of receptors in a novel, long-lived blocked state.

    “Moreover, our data on recovery from block are consistent with a model where fipronil-induced inhibition and channel desensitization proceed in parallel and independently, indicating that fipronil induces the accumulation of receptors in a novel, long-lived blocked state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    β3 homomeric receptors are unlikely to occur in great quantities in the brain and do not contribute to responses to endogenous GABA, making such receptors an unlikely target for fipronil in the CNS.

    “But the b3 homomeric receptors are unlikely to occur in great quantities in the brain and, in any case, they do not contribute to responses to the endogenous transmitter GABA (Wooltorton et al., 1997), making such receptors an unlikely target for fipronil in the CNS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wooltorton et al., 1997 source

  • May combine two claims.

    Interpretationown data

    Fipronil sulphone was less potent at inhibiting GABA_A receptor function, suggesting that conversion of fipronil to fipronil sulphone presents a detoxifying process in the mammalian brain.

    “The major metabolite of fipronil, fipronil sulphone was less potent at inhibiting the GABA A receptor function suggesting that the conversion of fipronil to fipronil sulphone presents a detoxifying process in the mammalian brain.”
    Quote in the paperSubstantial claim
32 of 32

  • The authors state this as an assumption.

    In the simplest model, the current decay rate in the presence of 1 mM GABA + 10 mM fipronil consists of the sum of the desensitization rate estimated in the absence of fipronil and the rate of fipronil-induced inhibition.

    “In the simplest model, the current decay rate in the presence of 1 mM GABA þ 10 mM fipronil (1/407 ms) consists of the sum of the desensitization rate (k þ D *) estimated in the absence of fipronil (1/5.6 s), and the rate of fipronil-induced inhibition (k on *).”

  • The authors state this as an assumption.

    Fipronil-induced block follows a second order reaction.

    “Assuming a second order reaction, the rate constant for the development of fipronilinduced block was 0.23 mM À1 s À1 (B2 Â 10 5 M À1 s À1 ).”

  • The paper relies on this without support.

    In both mammals and insects, fipronil is metabolized to fipronil sulphone.

    “In both mammals and insects, fipronil is metabolized to fipronil sulphone.”

  • The paper relies on this without support.

    Fipronil sulphone is a potent inhibitor of insect chloride channels.

    “Fipronil sulphone is a potent inhibitor of insect chloride channels”

  • The paper relies on this without support.

    The role of fipronil sulphone in mammalian toxicity is unclear.

    “but its role in mammalian toxicity is unclear.”
5 of 5

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting sulphone concentration in the recovery experiment

    Minor

    The Results text says recovery from sulphone-induced block was measured after exposure to 30 mM sulphone, but the Figure 8b caption describes the exposure as 10 mM.

  • Conflicting uncertainty for the Hill slope

    Minor

    The Results text gives the fitted Hill slope as 1.3 ± 0.2, while the Figure 2 caption gives 1.3 ± 0.1 for the same concentration-response fit.

2 of 2

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Authors
Li, P., & Akk, G.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Akk, G
ORCID
Akk, G
Venue
British Journal of Pharmacology
Publisher
Wiley
Published
2008-11
Volume
155
Issue
5
Pages
783-794
ISSN
  • 0007-1188 (ISSN-L)
  • 1476-5381
DOI
10.1038/bjp.2008.309
PMC
PMC2584928
OpenAlex
W1543268742
Cited by
33
References
35
Citations by year
2026: 2 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 2 · 2017: 1 · 2016: 1 · 2015: 2 · 2013: 1 · 2012: 3
FWCI
0.72
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 89 d)
Locations
  • British Journal of Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Environmental Health Sciences (R03ES016350, ES16350)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
fipronil, GABAA receptor, insecticide toxicity, receptor inhibition, channel block, channel desensitization, seizures
MeSH terms
Animals, Cell Line, Cloning, Molecular, Electrophysiology, Humans, Insecticides, Pyrazoles, Receptors, GABA-A, Recombinant Proteins, Molecular Structure, Ion Channel Gating, Patch-Clamp Techniques, Rats, GABA-A Receptor Antagonists

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