Loretta C. Gaughan

Substrate-specificity and toxicological significance of pyrethroid-hydrolyzing esterases of mouse liver microsomes☆

Abstract An esterase or esterases in acetone powder preparations of mouse liver microsomes hydrolyze the cyclopropanecarboxylate ester linkage of pyrethroid insecticide chemicals derived from primary alcohols. The rate of cleavage of (+)- trans -chrysanthemates with various alcohol moieties decreases in the following order: 5-propargyl-2-furylmethyl; 5-benzyl-3-furylmethyl (bioresmethrin); 3-phenoxybenzyl; tetrahydrophthalimidomethyl esters. The hydrolysis rate of benzylfurylmethyl esters with various acid moieties decreases in the order: (+)- or (−)- trans -chrysanthemate; (+)- trans -ethanochrysanthemate; tetramethylcyclopropanecarboxylate; (+)- or (−)- cis -chrysanthemate or (+)- cis -ethanochrysanthemate. The trans -isomers of chrysanthemates and ethanochrysanthemates are hydrolyzed from 2.6- to more than 50-fold more rapidly than the corresponding cis -isomers. This enzyme system does not hydrolyze secondary alcohol esters, i.e., allethronyl (+)- trans - and (+)- cis -chrysanthemates. On intraperitoneal administration to mice, the (+)- trans -chrysanthemate and -ethanochrysanthemate of benzylfurylmethanol are of very low toxicity relative to the corresponding (+)- cis -isomers and the tetramethylcyclopropanecarboxylate. S,S,S -tributyl phosphorotrithioate (DEF) pretreatment increases the toxicity of these five compounds by 2.6- to more than 188-fold, with the exception of bioresmethrin whose toxicity is not altered. When the toxicity is increased, it is probably the result of esterase inhibition since DEF strongly inhibits the esterase activity of fresh liver microsomes while the mixed-function oxidase system remains active. The oxidase system metabolizes the chrysanthemates more rapidly than the ethanochrysanthemates of benzylfuryl-methanol. Depending upon the pyrethroid involved, the esterase or the mixed-function oxidase system, or both may be responsible for limiting the toxicity of these pyrethroids to mice.

Structure-biodegradability relationships in pyrethroid insecticides

The metabolism of 20 pyrethroids has been examined to evaluate the contribution of detoxification in their selective action between insects and mammals. The studies utilized living houseflies, mice, or rats, or esterase and oxidase systems derived from these organisms. Pyrethroid-hydrolyzing esterases cleave the primary alcoholtrans- substituted-cyclopropanecarboxylates much faster than the correspondingcis-isomers but are ineffective in hydrolyzing secondary alcohol esters. Microsomal enzymes oxidize the (+)-trans-chrysanthemate moiety at thetrans-methyl group of the isobutenyl substituent and at one of the gem-dimethyl groups whereas the (+)-cis-isomer is attacked at either of the isobutenyl methyl groups. Products isomerized at C3 of the cyclopropane are also detected but only after ester cleavage and oxidation of an isobutenyl methyl group. Each alcohol moiety has its own unique sites for oxidation involving pentadienyl, allyl, benzylic methylene, and aromatic substituents. An enhancement of insecticidal activity is expected on replacement of the biodegradable groupings with substituents relatively resistant to metabolism but this may also increase the mammalian toxicity.

Metabolism of four resmethrin isomers by liver microsomes

Abstract Microsomal esterases of mouse and rat liver readily cleave the trans - but not the cis -isomers of resmethrin (5-benzyl-3-furylmethyl chrysanthemate). The ester linkage also appears to undergo oxidative cleavage when esterase attack is minimal, i.e., with (+)- cis - and particularly (−)- cis -resmethrin in microsome-NADPH systems and with any of the isomers when NADPH is added to microsomes pretreated with TEPP. Metabolites retaining the ester linkage are detected in significant amounts only with (+)- cis -resmethrin in which case they are formed by oxidation at either the trans (E)- or cis (Z)-methyl group of the isobutenyl moiety with or without oxidation of the benzylfurylmethyl group. Metabolites of each acid moiety include chrysanthemic acid and up to six derivatives of this acid formed by oxidation at the trans (E)- or cis (Z)-methyl group yielding the corresponding alcohol, aldehyde, or acid, with chrysanthemate isomer and enzyme source variations in the preferred site of oxidation. The major identified metabolite of the alcohol moiety is either benzylfurylmethanol or the corresponding carboxylic acid depending on the enzyme system used. In the course of microsomal oxidation, a fragment from the alcohol but not the acid moiety of (+)- trans - and (+)- cis -resmethrin is strongly bound to microsomal components. These findings confirm in vivo studies on the isomeric variations in metabolism of the resmethrin components.

Metabolism and degradation of the pyrethroids tralomethrin and tralocythrin in insects

Abstract Tralomethrin and tralocythrin undergo debromination, forming deltamethrin and cypermethrin, respectively, following topical administration to house flies, feeding to cabbage looper larvae, or incubation with house fly homogenates and cockroach nerve cords. The debromination is probably not an enzymatic process since it occurs rapidly on incubation with glutathione, cysteine, and albumin. Following debromination, an esterase(s) in house fly homogenate hydrolyzes delta-methrin and cypermethrin. The insecticidal activity of tralomethrin and tralocythrin may be due in part to the liberation of deltamethrin and cypermethrin in the insect or its nervous system.

Comparative Metabolism of Pyrethroids Derived from 3-Phenoxybenzyl and α-Cyano-3-Phenoxybenzyl Alcohols

Abstract Fenothrin, permethrin, Cypermethrin, decamethrin, fenpropanate and fenvalerate are highly insecticidal pyrethroids prepared by esterification of 3-phenoxybenzyl alcohol or α-cyano-3-phenoxybenzyl alcohol with chrysanthemic acid or other acids of similar configuration. These pyrethroids are rapidly metabolized in rats by hydrolysis and by oxidation at the 4′-position of the alcohol moiety and to a lesser extent at the aliphatic substituents. These sites are also involved in metabolism of the permethrin isomers in cows, chickens, insects, plants and soils, of decamethrin in mice and plants, and of fenvalerate in soils. Additional sites of oxidation of the permethrin isomers, decamethrin or fenvalerate in some animals are the 2′-, 5- and 6-positions of the alcohol moiety. Various combinations of oxidation, hydrolysis and conjugation lead to >50 identified metabolites of the permethrin isomers in various insects and mammals. In vitro studies with microsomal oxidase preparations from mammals, insects and fish reveal some or all of these sites of hydroxylation and further oxidation of the hydroxymethyl substituents to the corresponding aldehydes and carboxylic acids. The selective toxicity of pyrethroids between insects and mammals may be further increased by replacing substituents biodegraded rapidly in insects with others more resistant to insect but not mammalian pyrethroid carboxyesterases and microsomal oxidases.