Permethrin hydrolysis

Ester hydrolysis occurs to a larger extent with the trans and primary alcohol derivatives as compared with the corresponding cis and secondary alcohol derivatives, respectively (Fig. 2). The chirality (1 S or 1R) at the acid moiety of phenothrin [9], tetramethrin [10], and permethrin [11] does not significantly affect ester hydrolysis. 

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. 

Nakamura Y, Sugihara K, Sone T, Isobe M, Ohta S, Kitamura S (2007) The in vitro metabolism of a pyrethroid insecticide, permethrin, and its hydrolysis products in rats. Toxicology 235 176-184... 

Yang D, Pearce RE, Wang X, Gaedigk R, Wan YJ, Yan B (2009) Human carboxylesterases HCE1 and HCE2 ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem Pharmacol 77 238-247... 

CASRN 52645-53-1 molecular formula C21H20CI2O3 FW 391.29 Soil. Permethrin biodegraded rapidly via hydrolysis yielding 3-(2,2-dichloroethenyl)-2,2-di-methylcyclopropanecarboxylic acid and 3-phenoxybenzyl alcohol (Kaufman et al., 1981). The reported half-life in soil containing 1.3-51.3% organic matter and pH 4.2-7.7 is <38 d (Worthing and Hance, 1991). 

Derivatives of chrysanthemic acid such as (H ,3f )-permethrinic acid 143 are in demand for the manufacture of highly specific insecticides that do not persist in the environment. Mixtures of the esters 142 are easy to make and contain various proportions of the cis and trans diastereoisomers. Pig liver esterase accepts only the trans esters as substrates so complete hydrolysis gives the unchanged cis esters and hydrolysed but poorly resolved trans acids. At 50% conversion, kinetic resolution of the trans esters occurs.36... 

Hydrolases. Hydrolytic mechanisms are also important in insecticide resistance, despite the apparent low activities in resistant insects when compared to mammalian enzymes (Table III). Some strains of resistant mosquitoes (22), Tribolium beetles (24), and Indianmeal moth (22) have specific resistance for malathion and similar carboxylester insecticides. This is due to increased catalytic hydrolysis, possibly through production of a more efficient enzyme (25.26). Californian tobacco budworms with low level permethrin resistance exhibited twice the normal activity of trans-permethrin carboxylester hydrolase (27). 

It is clear that the insecticide of interest must be used to assay for this type of resistance since 1-naphthyl acetate, a general substrate used to stain for many hydrolases, did not detect malathion carboxylester hydrolase (assayed as the hydrolysis of [14C]-malathion) in starch gel electrophoresis of Culex tarsalis (23). Similarly, trans-permethrin hydrolyzing activity of soybean looper was resolved from 1-naphthyl acetate hydrolyzing activity by polyacrylamide gel electrophoresis (28). Malathion carboxylester hydrolases were not correlated with activity toward 1-naphthyl acetate in Drosophila, Anopheles, and Indianmeal moth (25.29.30). 

Show the compounds that would result if pyrethrin I and permethrin were to undergo hydrolysis. 

Permethrinic acid Table B33, Appendix B, gives the four isomers arising from the hydrolysis of the four isomers of permethrin and the eight isomers of cypermethrin and cyfluthrin. 

In a rat study involving the two isomers of bifenthrin, the major metabolites found in rat plasma (Smith et al. 2002 TuUman 1987) were the parent compound, the hydrolysis product, 2-MBP alcohol, [l l-biphenyl]-3-methanol, 2-methyl (CAS no. 76350-90-8), and the oxidized product of the alcohol, 2-MBP acid, [1,1 -biphenyl]-3-carboxylic acid (CAS no. 115363-11-6). The 2-MBP acid compound is analogous to 3-phenoxybenzoic acid (CAS no. 3739-38-6), the hydrolysis product of cypermethrin, deltamethrin, permethrin, and fenvalerate (Huckle et al. 1981a, b, 1984 lARC 1991 Woollen et al. 1992). In addition to these ester-cleaved products, 4 -OH, 2-MBP alcohol (CAS no. 115340-46-0) and 4 -OH, 2-MBP acid (CAS no. NA) were found. According to Kaneko (2010), these metaboUtes are metaboUcaUy converted to dimethoxy 2-MBP alcohol and dimethoxy 2-MBP acid. 

Lactonization occurred during treatment with strong acids or as artifacts of TLC separations. The glucuronides were partially converted to lactone derivatives when dilute methanolic HCL solutions were evaporated to dryness. Ninety-seven to hundred percent of the two mixed cfr-permethrin isomers and the two mixed trans isomers ( C-acid and alcohol labeled) were recovered in urine and feces. The hydrolysis products of ( C-acid-lR, trans) and ( " C-alcohol-lR, trans) permethrin were largely eliminated in urine (81-90%), while only 45-54% from aT-permethrin appeared in urine. The glucuronide of CI2CA was the principal metabolite found in the urines of (IR, trans 56.1%) and (IRS, trans 41.9%) permethrin-treated rats, while a lesser amount were found in the urines of (IR, cis 18.5%) and (IRS, cis 13.8%) permethrin-administered rats. For rats administered the C-alcohol-labeled permethrin, the principal metabolite was 4-OH PB acid sulfate in urine of rats administered (IR, trans 30.7%) and (IRS, trans 42.8%) permethrin. Less of this metabolite was found in urine of rats administered the (IR, cis 19.5%) and (IRS, cis 29.3%) permethrin. 

Choi and Soderlund (2006) identified human alcohol (ADH) and aldehyde dehydrogenases (ALDH) as the enzymes involved in the oxidation of PB alcohol (phenoxybenzyl alcohol) from trans-permethrin to PB acid (phenoxybenzoic acid) via phenoxybenzaldehyde. C -Permethrin was not metabolized to any extent in human liver fractions. Cytochrome P450 isoforms were not involved either in the hydrolysis of traws-permethrin or in the oxidation of the PB alcohol to the PB acid. 

Ross et al. (2006) studied the hydrolytic metabolism of Type 1 pyrethroids (bioresmethrin, IRS fraws-permethrin, and IRS c/s-permethrin) and several Type II pyrethroids (alpha-cypermethrin and deltamethrin) by pure human CEs (hCE-1 and hCE-2), a rabbit CE (rCE), and two rat CEs (Hydrolases A and B). Hydrolysis rates were based on the formation of 3-phenoxybenzyl alcohol (PBAlc) (CAS no. 13826-36-2) for the cis and trans isomers of permethrin. For bioresmethrin, hydrolysis was based on the production of the trans-chrysanthemic acid (CPCA) (CAS no. 10453-89-1). For alpha-cypermethrin and deltamethrin, hydrolysis was based on the formation of c/s-permethrinic acid (DCCA) (CAS no. 57112-16-0) and 3-phenoxybenzyl aldehyde (PBAld CAS no. 39515-51-0), respectively. Human CE-1 and hCE-2 hydrolyzed trans-permethrin 8- and 28-fold more efficiently (based on kcat/Km values) than did c/s-permethrin, respectively. The kinetic parameters (Fmax> for the hydrolysis of trans- and c/s-permethrin, bioresmethrin and alpha-cypermethrin by rat, mouse, and human hepatic microsomes are given in Table 7. The trans- isomer of permethrin is more readily hydrolyzed by rat, mouse and human hepatic microsomal carboxylesterase than c/s-permethrin (13.4, 85.5 and 56.0 times, respectively). However, the lower for hydrolysis of cis-permethrin in human microsomes suggests that there are both stereoisomer and species-specific differences in metabolism kinetics. 

The relative levels of hCE-1 protein were measured in human microsomes by immunoblotting to determine if variation in hydrolytic metabolism was related to the abundance of hCE-1 in the microsomes. Human CE-1 levels did not correlate (r = 0.294) well with F ,ax values for the hydrolysis of Irans-permethrin. Esterases other than hCE-1 are believed to be responsible for the different values. CDMB (1,2-ethanedione, l-(2-chlorophenyl)-2-(3,4-dimethoxyphenyl)-(CAS no. 56159-70-7)) was used to inhibit the activity of hCE-2 (Wadkins et al. 2005). 

The metabolism of bifenthrin, S-bioallethrin, and crs-permethrin in rat and human hepatic microsomes was the result of oxidative processes, while the metabolism of bioresmethrin and cypermethrin in human hepatic microsomes was hydrolytic (not shown in Table 8). Cypermethrin and bioresmethrin were metabolized by oxidation and hydrolysis in rat hepatic microsomes. Tra/j -permethrin and (3-cyfluthrin were metabolized by both pathways in human and rat hepatic microsomes. 

Fig. 11 Comparison of the turnover numbers ( cat) for human CE (hCE-1) and rat CE (hydrolase A). Hydrolysis of c/ -permethrin, tra Z5-permethrin, and bioresmethrin are from Ross et al. (2006), while similar information for esfenvalerate and deltamethrin are from Godin et al. (2006). This figure is published with permission (Godin et al. 2006)...

The 3D QSAR pharmacophore model selected very fast and very slow metabolizers, leaving the catalytic hydrolysis rates in the middle group as being questionable. Catalytic rates ( cat) for the pyrethroids that were outside of the training set (8-25 h ) were obtained by extrapolation. Less confidence should be placed on these predicted values. The hydrolysis rate for deltamethrin (IR, cis, aS) fell into the middle group and was not included in Table 19. However, catalytic rates (rat serum carboxylesterases) for two trans deltamethrin (1R,3S, aR lS,3R,oR) isomers were included in the table and compared favorably with the rat hydrolase A and B values in Table 11. Cypermethrin (IR, trans, aR), cyfluthrin (IR, trans, oR IR, trans, oR), and permethrin (IR, trans IS, trans) were fast metabolizers. Among the slow metabolizers were permethrin (IS, cis), cyfluthrin (IS, cis, aS) and cypermethrin (IR, trans, aS). 

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. 

Using the parent compound depletion method, pyrethroid metabolic rate constants (i.e., Umax and K, hast, etc.) for hydroxylation by cytochrome P450 enzymes or hydrolysis by carboxylesterases were developed by Scollon et al. (2009). The sources of the enzymes were rat and human microsomes. The pyrethroids they studied included bifenthrin, S-bioallethrin, bioresmethrin, p-cyfluthrin, cypermethrin, cis-permethrin, and frans-permethrin. The depletion method considers multiple hydroxylations as a single biotransformation at sites on either the acid or alcohol moieties, or on a combination of both. The metabolic pathways (Tables D1-D15 and E1-E15 of Appendices D and E, respectively) require Umax, Am, and values for the individual hydroxylated and hydrolyzed products. It is interesting that only bioresmethrin and cypermethrin per se were found to actually be hydrolyzed. 

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