Trans-permethrin

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. 

It was reported that the distribution and activities of esterases that catalyze pyrethroid metabolism using several human and rat tissues, including small intestine, liver, and serum, were examined [30]. The major esterase in human intestine was hCE2. //c/n.v-Permethrin was effectively hydrolyzed by pooled human intestinal microsomes (five individuals), while deltamethrin and bioresmethrin were not. This result correlated well with the substrate specificity of recombinant hCE2. In contrast, pooled rat intestinal microsomes (five animals) hydrolyzed trans-permethrin 4.5 times slower than the human intestinal microsomes. Furthermore, pooled samples of cytosol from human or rat liver were ca. half as hydrolytically active as the corresponding microsome fraction toward pyrethroids however, the cytosolic fractions had significant amounts (ca. 40%) of the total hydrolytic activity. Moreover, a sixfold interindividual variation in hCEl protein expression in human hepatic cytosols was observed. 

Takaku T, Mikata K, Matsui M, Nishioka K, Isobe N, Kaneko H (2011) In vitro metabolism of trans-permethrin and its major metabolites PBalc and PBacid, in humans. J Agric Food Chem 59 5001-5005... 

Figure 8.3. Separation of synthetic pyrethroids (0.8 ng of each) on a 25 m OV-101 WCOT capillary column. Peaks 1 = cis-methrin 2 = bioresmethrin 1 + 2 = resmethrin 4 and 5 = phenothrin 6 = cis-permethrin 7 = trans-permethrin 8, 9, 10 and 11 = cypermethrin 12 and 13 = fenvalerate and 14 and 15 = deltamethrin. From [80]...

Pest control agent cis-/trans-permethrin, deltamethrin, 1 pyrethrum, piperonylbutoxid... 

Chemical materials. Ring-labelled C fenitrothion was supplied by the Sumitomo Chemical Co., Osaka, Japan (20.23 uCi/uM). Aminocarb was obtained from Mobay Chemical Co., Kansas City, Mo., USA, as ring-labelled C material (11.7 uCi/uM). Cis- and trans- permethrin were synthesized as methylene- C compounds (59.7 uCi/uM), or as cyclopropyl- C compounds (50 uCi/uM) by ICI Ltd., Jealotts Hill, UK. Fluorene was purchased as 9- C material from California Bionuclear Corp. (2.61 uCi/uM). 

Figure lb. Uptake and depuration curves for cis- and trans-permethrin in laboratory studies with larval rainbow trout. 

Carboxylesterases are responsible for the selective toxicity of malathion that favors mammals over insects. Carboxylesterase hydrolyzing trans-permethrin has been found in numerous insect species, including the fall armyworm, velvetbean caterpillar (Anticar-sia gemmatalis), cabbage looper (Trichoplnsia ni), tobacco budworm (Heliothis virescens), corn earworm (Helicoverpa zea), and spined soldier bug (Podisus maculwentris) (Yu, 1990). 

Figure 8.28 Metabolic pathways of trans-permethrin in animals, a-d indicate oxidative metabolic sites. The white arrow indicates esterase action. (From Matsu mu ra, F., Toxicology of Insecticides, 2nd ed., Plenum Press, New York, 1985. With permission.)...

Glickman, A.H., S.D. Weitman and J.J. Lech. Differential toxicity of trans-permethrin in rainbow trout and mice. I. Role of biotransformation. Toxicol. Appl. Pharmacol. 66 153-161, 1982. 

Organophosphate resistance in M. persicae is due to the production of large amounts of carboxylesterase E4 that degrade as well as sequester these insecticides (12). This is believed to be the only biochemical resistance mechanism in this species in many countries, including the UK., continental Europe, Japan, and Australia (25.). E4 additionally confers low levels of resistance to carbamates and to (IS)-trans-permethrin (12). This esterase has been characterized extensively by toxicological, biochemical, immunological and molecular studies (2, 22, 22f 22, 22) ... 

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). 

Sidon, E.W., Moody, R.R, and Franklin, C.A. (1988). Percutaneous absorption of cis- and trans-permethrin in rhesus monkeys and rats anatomic site and interspecies variation, J. Toxicol. Environ. Health, 23(2), 207-216. 

The decrease in the concentration of cis and trans-permethrin along die runoff padi was similar to that of bifenthrin (Figure 6). The greatest decrease occurred after the sediment trap, but further reduction occurred also in the vegetated channel. On 05/16/2002, the initial cu-permethrin level was 24.5 pg... 

Figure 6, Reduction in permethrin concentration in runoff at different locations, (A) cis-permethrin (B) trans-permethrin.

Permethrin Table B19, Appendix B, gives the chiral configurations of the four individual isomers of permethrin, their optical rotation, CAS no. for absolute stereochemistry, and enantiomer pairs. The structure of each stereoisomer is coded A-D making it easier to identify (label) each isomer. Table B20, Appendix B, lists permethrin, cw-permethrin, tran -permethrin, and biopermethrin as technical products sold by registrants. Technical permethrin contains all four isomers, while cis/trans permethrin contains isomers A, D and B, C, respectively. Biopermethrin contains only isomer B . 

Permethrinic acid has two enantiomer pairs and four isomers (2" = 4) (Table B33, Appendix B). The acid leaving group for permethrin, cypermethrin, and cyfluthrin is permethrinic acid. The structure of this acid is given in Table 3. Angerer and Ritter (1997) separated the methyl esters of cis- and trans-permethrinic acid on a polysiloxane capillary column by GC (Table C18, Appendix C). The carboxylic acids of several of these pyrethroids were also listed as trans- or cw-3-(2, 2-dichlorovinyl)-2, 2-dimethyl cyclopropane carboxylic acid. The acids may be separated on a CHIREX phase 3005 column (Phenomenex, 2320 W 205th Street, Torrance, CA 90501) by HPLC. 

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. 

Rat serum was found capable of hydrolyzing the six pyrethroids studied by Crow et al. (2007), with bioresmethrin and trans-permethrin being hydrolyzed the fastest and cA-permethrin, deltamethrin and esfenvalerate the slowest. Humans lack detectable amounts of CEs in blood. On this basis, the rat should be considered a poor surrogate animal for human health risk assessment at the environmentally low levels at which the pyrethroids normally exist (Crow et al. 2007). 

Table ElO Biotransformation and elimination paths of trans-permethrin and the resulting...

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