Oxidative metabolism pyrethroids

Mixtures of PBO with pyrethroid or carbamate insecticides are often more effective against insect strains resistant to these compounds where oxidative metabolism is responsible for the decreased effect (Davies et at., 1958 Wilkinson, 1968 Glynne-Jones, 1983 MacDonald eta ., 1983 h unaki etai. 1986). There is no evidence to indicate that PBO increases the low toxicity of pyrethrins and pyrethroids l<> mammals. The acceptable daily intake (ADI) of PBO for humans has been established at 0.2 mg per kg body weight (JMPR, 1995),... 

Keywords Carboxylesterase CYP Ester hydrolysis Metabolism Oxidation Pyrethroid... 

Extensive metabolism studies carried out mainly in rats and mice show that pyrethroids are metabolized by oxidation and ester cleavage, which are mediated by CYP isoforms and carboxylesterases, respectively. CYP isozymes and carboxylesterases responsible for the metabolism are reviewed below. 

In chemical-specific parameters used for PBPK modeling, the metabolic rate constant is crucial to the accuracy of modeling results in many cases. For some pyrethroids, hydrolysis in intestine and serum has a significant role in the metabolism of the compound in mammals besides oxidation and ester cleavage in liver, which is the most important organ for detoxification of many chemicals. 

The typical metabolic reactions of pyrethroids are hydrolysis of an ester linkage and oxidation of an alkyl group or an aromatic ring in either acid or alcohol moiety, as shown in Fig. 6. The oxidative cleavage of the C=C bond of the prop-l-enyl... 

Particularly characteristic of the metabolism of pyrethroids in the insects are oxidative conversions. Yamamoto et al. (1969) have shown that one of the two methyl groups of the isobutenyl side-chain is oxidised to a hydroxymethyl group. 

Metabolism. The wide acceptance and enormous usefulness of the pyrethrum and pyrethroids are that they pose to be highly toxic particularly to the ectoparasites, whereas they prove to be comparatively much less toxic i.e., nontoxic) to mammals in case absorbed. The magnificent notoxic characteristic feature is associated with the excellent and rapid metabolism of these drug substances either via hydrolysis or oxidation. More specifically, the extent of either hydrolysis or oxidation is exclusively dependent upon the structure of the prevailing pyrethrins or pyrethroids. 

Fenvalerate and other a-cyano pyrethroids, however, are consistently more resistant to oxidative attack than their noncyano analogs. Liver is the predominant site of fenvalerate metabolism via hydrolysis by one or more hepatic microsomal esterases inhibition of these enzymes results in enhanced toxicity. Hydrolysis has also been demonstrated in plasma, kidney, stomach, and brain tissues. Except for brain, however, these tissues were relatively unimportant in the detoxification process. 

Oncorhynchus mykiss) - one of the more sensitive aquatic species - have significantly lower rates of metabolism and elimination of fenvalerate than those reported for birds and mammals show little or no esterase activity towards pyrethroids and substantially lower oxidative activity than warm-blooded animals efficiently accumulate fenvalerate from the medium, and show greater intrinsic sensitivity of the central nervous system when compared with birds and mammals. 

Hydrolysis of the pyrethroids may occur prior to hydroxylation. For dichloro groups (i.e., cyfluthrin, cypermethrin and permethrin) on the isobutenyl group, hydrolysis of the trans-isomers is the major route, and is followed by hydroxylation of one of the gem-dimethyls, the aromatic rings, and hydrolysis of the hydroxylated esters. The cis-isomers are not as readily hydrolyzed as the tran -isomers and are metabolized mainly by hydroxylation. Metabolism of the dibromo derivative of cypermethrin, deltamethrin, is similar to other pyrethroids (i.e., cyfluthrin, cypermethrin, and permethrin) that possess the dichloro group. Type 11 pyrethroid compounds containing cyano groups (i.e., cyfluthrin, cypermethrin, deltamethrin, fenvalerate, fenpropathrin, and fluvalinate) yield cyanohydrins (benzeneacetonitrile, a-hydroxy-3-phenoxy-) upon hydrolysis, which decompose to an aldehyde, SCN ion, and 2-iminothia-zolidine-4-carboxylic acid (TTCA). Chrysanthemic acid or derivatives were not used in the synthesis of fenvalerate and fluvalinate. The acids (i.e., benzeneacetic acid, 4-chloro-a-(l-methylethyl) and DL-valine, Af-[2-chloro-4-(trifluoromethyl) phenyl]-) were liberated from their esters and further oxidized/conjugated prior to elimination. Fenpropathrin is the oifly pyrethroid that contains 2,2,3,3-tetramethyl cyclopropane-carboxylic acid. The gem-dimethyl is hydroxylated prior to or after hydrolysis of the ester and is oxidized further to a carboxylic acid prior to elimination. 

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