Metabolism of Pyrethroids

Source Data from Envfronmental Health Criteria 82, Envfronmental Health Criteria 94, Environmental Healhi Criteria 95, Environmental Healhi Criteria 97, and Environmental Health Criteria 142. 

Organic Pollutants An Ecotoxicological Perspective, Second Edition 

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The metabolism of permethrin will be taken more generally as an example of the metabolism of pyrethroids (Figure 12.2). The two types of primary metabolic attack are by microsomal monooxygenases and esterases. Monooxygenase attack involves... 

Table 1 Cytochrome P450s and carboxylesterases responsible for metabolism of pyrethroids... 

These in vivo and in vitro human metabolism studies indicate that pyrethroids undergo rapid metabolism and elimination as observed in rats, and qualitative metabolic profiles (e.g., kinds of metabolites) of pyrethroids are assumed to be almost the same between humans and rats, suggesting that a large database of animal metabolism of pyrethroids could provide useful information for the evaluation of behavior of pyrethroids in humans. Nowadays, human pesticide dosing studies for regulatory propose are severely restricted in the US, and thus detailed comparison of in vitro metabolism (e.g., metabolic rate constants of pathways on a step-by-step basis) using human and animal tissues could be an appropriate method to confirm the similarity or differences in metabolism between humans and animals. 

Scollon EJ, Starr JM, Godin SJ, DeVito MJ, Hughers MF (2009) In vitro metabolism of pyrethroid pesticides by rats and human hepatic microsomes and cytochrome p450 isoforms. Dmg Metab Dispos 37 221-228... 

Ross MK, Borazjani A, Edwards CC, Potter PM (2006) Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterases. Biochem Pharmacol 71 657-669... 

Fig. 9 In vitro metabolism of pyrethroid metabolites in leaf cell suspension of cabbage (C) and tomato (T). The values in parentheses are percent of the total radioactive residues in leaf cell extract/medium after 1-day incubation, nd not detected...

Many investigations of relevant enzymes in transformation of xenobiotics by aquatic species have shown that the similar enzymes observed in metabolism in soil, plant, and mammals play a role, such as esterases and oxidases [10, 159, 160]. Metabolism of pyrethroids has been most extensively studied in fish for cypermethrin (5) and permethrin (15). Aromatic hydroxylation at the 4 -position of the 3-phenoxybenzyl moiety followed by conjugation with glucuronic acid... 

Demon te, J-P. (1989). A brief review of the environmental fate and metabolism of pyrethroids. Pcsiic. Sci. 27, 375-385. 

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. 

Tyler, C.R., Beresford, N., and van der Woning, M. et al. (2000). Metabolism and environmental degradation of pyrethroid insecticides produce compounds with endocrine activities. Environmental Toxicology and Chemistry 19, 801-809. 

Metabolism of the 2,S -isomers proceeds sequentially hydroxylation at the phenoxy group, hydrolysis of the cyano group, and cleavage of the ester linkage (Coats et al. 1989). Fenvalerate and the IS-isomers yield two ester metabolites in feces from hydroxylation at the 4 - and 2 -phenoxy positions. Other significant metabolites were 3-phenoxybenzoic acid and its hydroxy derivatives from the alcohol moiety, 3-(4-chlorophenyl) isovaleric acid and its hydroxy derivatives from the acid moiety, and thiocyanate and carbon dioxide from the cyano moiety (Ohkawa et al. 1979). A slow elimination rate characterizes fenvalerate and other a-cyano pyrethroids when compared with... 

Golenda, C.F. and A.J. Forgash. 1989. The distribution and metabolism of fenvalerate in pyrethroid-resistant and susceptible house flies. Pestic. Biochem. Physiol. 33 37-48. 

Riviere, J.L., J. Bach, and G. Grolleau. 1983. Effect of pyrethroid insecticides and N-(3,5-dichlorophenyl) dicarboximide fungicides on microsomal drug-metabolizing enzymes in the Japanese quail (Cotumix cotumix). Bull. Environ. Contam. Toxicol. 31 479-485. 

This chapter presents an overview of mammalian metabolic fates of pyrethroids, enzymes responsible for biotransformation, human metabolism and species, isomers, and age differences of pyrethroids. 

Pure human CESs (hCEl and hCE2), a rabbit CES (rCE), and two rat CESs (Hydrolases A and B) were used to study the hydrolytic metabolism of the following pyrethroids lR-trans-resmethrin (bioresmethrin), 1RS-1runs-permethrin, and 1RS-r/.v-pennethrin [28], hCEl and hCE2 hydrolyzed /ram-pemiethrin 8- and 28-fold more efficiently than m-permethrin (when kcat/Km values were compared), respectively. In contrast, hydrolysis of bioresmethrin was catalyzed efficiently by hCEl, but not by hCE2. The kinetic parameters for the pure rat and rabbit CESs were qualitatively similar to the human CESs when hydrolysis rates of the investigated pyrethroids were evaluated. Further, a comparison of pyrethroid hydrolysis by hepatic microsomes from rats, mice, and humans indicated that the rates for each compound were similar between species. 

The serum CES was purified to homogeneity to determine its contribution to pyrethroid metabolism in the rat [30]. Both trans-permethrin and bioresmethrin were effectively cleaved by this serum CES, but deltamethrin, esfenvalerate, a-cypermethrin, and m-permethrin were slowly hydrolyzed. Two model lipases produced no hydrolysis products from pyrethroids. These results demonstrated that extrahepatic esterolytic metabolism of specific pyrethroids might be significant. 

No explicit sex-related difference in ester cleavage of pyrethroids was reported in pyrethroid metabolism in mammals. 

When evaluating the safety of chemicals in humans, it is very important to know the fate of chemicals in the human body and the amounts of exposure in daily activity. This section reviews the metabolic reactions of pyrethroids in humans, and the biomonitoring of pyrethroid metabolites in human urine for the exposure assessment. Mathematical modeling is a useful tool to predict the fate of chemicals in humans. This section also deals with the recent advance of mathematical modeling of pyrethroids to predict the pharmacokinetics of pyrethroids. 

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. 

Crawford MJ, Croucher A, Hutson DH (1981) The metabolism of the pyrethroid insecticide cypermethrin in rats excreted metabolites. Pestic Sci 12 399—411... 

Casida JE, Ruzo LO (1980) Metabolic chemistry of pyrethroid insecticides. Pestic Sci 11 257-269... 

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