The relationship between brain levels of cismethrin and bioresmethrin in female rats and neurotoxic effects

White, Ian N.H.; Verschoyle, Richard D.; Moradian, Maryam; Barnes, J. M.

doi:10.1016/0048-3575(76)90060-2

Cited by 56 publications

(29 citation statements)

References 13 publications

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“…The toxicity of pyrethroids to insects and cold-blooded vertebrates shows a negative temperature coefficient and lowering of the temperature causes the appearance of toxic sign^.^^-^' The latter effect is rapidly re~ersible'~ and parallels the further prolongation of the pyrethroid-induced sodium tail current on cooling in v i t r~.~.~' In homeothermic animals the effect of changes in environmental temperature appears more complex as reflected by the negative temperature coefficient of oral but not of intravenous toxicity of cismethrin to the rat. 79 In conclusion, pyrethroids prolong the open time of voltagedependent sodium channels, resulting in a prolongation of the inward sodium current during excitation. This effect not only accounts for the repetitive activity in sense organs, but also for membrane depolarization, suppression of the amplitude of the nerve impulse, and block of excitation that may occur in various parts of the nervous system.…”

Section: T(s)mentioning

confidence: 99%

Neurotoxicological Effects and the Mode of Action of Pyrethroid Insecticides

Vijverberg¹,

Bercken²

1990

Critical Reviews in Toxicology

344

137

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Neuroexcitatory symptoms of acute poisoning of vertebrates by pyrethroids are related to the ability of these insecticides to modify electrical activity in various parts of the nervous system.Repetitive nerve activity, particularly in the sensory nervous system, membrane depolarization, and enhanced neurotransmitter release, eventually followed by block of excitation, result from a prolongation of the sodium current during membrane excitation. This effect is caused by a stereoselective and structure-related interaction with voltage-dependent sodium channels, the primary target site of the pyrethroids.Near-lethal doses of pyrethroids cause sparse axonal damage that is reversed in surviving animals. After prolonged exposure to lower doses of pyrethroids axonal damage is not observed.Occupational exposure to pyrethroids frequently leads to paresthesia and respiratory irritation, which are probably due to repetitive firing of sensory nerve endings. Massive exposure may lead to severe human poisoning symptoms, which are generally treated well by symptomatic and supportive measures.

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Section: T(s)mentioning

confidence: 99%

Neurotoxicological Effects and the Mode of Action of Pyrethroid Insecticides

Vijverberg¹,

Bercken²

1990

Critical Reviews in Toxicology

344

137

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“…Thus, the neurotoxicity of pyrethrins and pyrethroids is produced by the parent chemical (Narahashi, 1985;Smith et al, 1997). Furthermore, the toxic potency of pyrethroids in mammals is inversely related to their rates of metabolic elimination (Abernathy and Casida, 1973;White et al, 1976).…”

mentioning

confidence: 99%

Identification of Rat and Human Cytochrome P450 Isoforms and a Rat Serum Esterase That Metabolize the Pyrethroid Insecticides Deltamethrin and Esfenvalerate

Godin

Crow²,

Scollon³

et al. 2007

Drug Metab Dispos

123

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ABSTRACT:The metabolism of (␣S)-cyano-3-phenoxybenzyl (1R, 3R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylate (deltamethrin) and (␣S)-cyano-3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutyrate (esfenvalerate) by rat and human liver microsomes differs with respect to the biotransformation pathway (oxidation versus hydrolysis) responsible for their clearance. This study aims to further explore the species differences in the metabolism of these chemicals. Using a parent depletion approach, rat and human cytochromes P450 (P450s) were screened for their ability to eliminate deltamethrin or esfenvalerate during in vitro incubations. Rat P450 isoforms CYP1A1, CYP2C6, CYP2C11, and CYP3A2 and human P450 isoforms CYP2C8, CYP2C19, and CYP3A5 were capable of metabolizing either pyrethroid. Human CYP2C9 metabolized esfenvalerate but not deltamethrin. Rat and human P450s that metabolize esfenvalerate and deltamethrin do so with similar kinetics. In addition to the liver, a potential site of metabolic elimination of pyrethroids is the blood via serum carboxylesterase (CE) hydrolysis. The serum of rats, but not humans, contains significant quantities of CE. Deltamethrin and esfenvalerate were metabolized effectively by rat serum and a purified rat serum CE. In contrast, neither pyrethroid was metabolized by human serum or purified human serum esterases (acetylcholinesterase and butyrylcholinesterase). These studies suggest that the difference in rates of oxidative metabolism of pyrethroids by rat and human hepatic microsomes is dependent on the expression levels of individual P450 isoforms rather than their specific activity. Furthermore, these studies show that the metabolic elimination of deltamethrin and esfenvalerate in blood may be important to their disposition in rats but not in humans.

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“…The adverse effects produced by pyrethroids are due to the parent compounds in that no evidence currently exists that pyrethroid metabolites alter sodium channels and are neurotoxic. For the limited number of pyrethroids evaluated, the brain concentrations of pesticide appear to correlate with acute neurotoxicity (White et al, 1976;Rickard and Brodie, 1985). Pharmacokinetic parameters, particularly clearance of the parent chemical from the blood, will influence the effective concentration in the brain and therefore can have a significant influence on their toxic potency.…”

mentioning

confidence: 99%

Species Differences in the in Vitro Metabolism of Deltamethrin and Esfenvalerate: Differential Oxidative and Hydrolytic Metabolism by Humans and Rats

Godin¹,

Scollon²,

Hughes³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Pyrethroids are neurotoxic pesticides whose pharmacokinetic behavior plays a role in their potency. This study examined the elimination of esfenvalerate and deltamethrin from rat and human liver microsomes. A parent depletion approach in the presence and absence of NADPH was used to assess species differences in biotransformation pathways, rates of elimination, and intrinsic hepatic clearance. Esfenvalerate was eliminated primarily via NADPH-dependent oxidative metabolism in both rat and human liver microsomes. The intrinsic hepatic clearance (CL INT ) of esfenvalerate was estimated to be 3-fold greater in rodents than in humans on a per kilogram body weight basis. Deltamethrin was also eliminated primarily via NADPH-dependent oxidative metabolism in rat liver microsomes; however, in human liver microsomes, deltamethrin was eliminated almost entirely via NADPHindependent hydrolytic metabolism. The CL INT for deltamethrin was estimated to be 2-fold more rapid in humans than in rats on a per kilogram body weight basis. Metabolism by purified rat and human carboxylesterases (CEs) were used to further examine the species differences in hydrolysis of deltamethrin and esfenvalerate. Results of CE metabolism revealed that human carboxylesterase 1 (hCE-1) was markedly more active toward deltamethrin than the class 1 rat CEs hydrolase A and B and the class 2 human CE (hCE-2); however, hydrolase A metabolized esfenvalerate 2-fold faster than hCE-1, whereas hydrolase B and hCE-1 hydrolyzed esfenvalerate at equal rates. These studies demonstrate a significant species difference in the in vitro pathways of biotransformation of deltamethrin in rat and human liver microsomes, which is due in part to differences in the intrinsic activities of rat and human carboxylestersases.Pyrethroids are synthetic analogs of the natural pyrethrins, the insecticidal components of extracts from the pyrethrum flower (Chrysanthemum cinerariaefolium). The pyrethroids modulate nerve axon sodium channels, resulting in neurotoxic effects (Narahashi, 1985;Smith et al., 1997). The adverse effects produced by pyrethroids are due to the parent compounds in that no evidence currently exists that pyrethroid metabolites alter sodium channels and are neurotoxic. For the limited number of pyrethroids evaluated, the brain concentrations of pesticide appear to correlate with acute neurotoxicity (White et al., 1976;Rickard and Brodie, 1985). Pharmacokinetic parameters, particularly clearance of the parent chemical from the blood, will influence the effective concentration in the brain and therefore can have a significant influence on their toxic potency.The metabolic pathway and rate of phase I biotransformation of pyrethroids are dependent upon their chemical structure and stereochemistry (Ueda et al., 1975;Soderlund and Casida, 1977;Shono et al, 1979). In laboratory animals, different metabolic pathways preferentially transform cis-and trans-isomers of pyrethroids; transisomers are typically transformed by the more rapid hydrolytic pathways, whereas ...

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The relationship between brain levels of cismethrin and bioresmethrin in female rats and neurotoxic effects

Cited by 56 publications

References 13 publications

Neurotoxicological Effects and the Mode of Action of Pyrethroid Insecticides

Neurotoxicological Effects and the Mode of Action of Pyrethroid Insecticides

Identification of Rat and Human Cytochrome P450 Isoforms and a Rat Serum Esterase That Metabolize the Pyrethroid Insecticides Deltamethrin and Esfenvalerate

Species Differences in the in Vitro Metabolism of Deltamethrin and Esfenvalerate: Differential Oxidative and Hydrolytic Metabolism by Humans and Rats

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