Deltamethrin hydrolysis, carboxylesterase

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. 

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... 

Table 11 Hydrolysis of deltamethrin kinetic parameters of human and rat carboxylesterases...

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). 

This information was used to cmistruct a PBPK/PD model in the adult male rat (MirfazaeUan et al. 2006). Godin et al. (2006) examined species differences between rat and human liver microsomal carboxylesterases. A significant species difference was noted in the in vitro biotransformation of deltamethrin, due in part to differences in the rate of hydrolysis by human liver microsomes. Godin et al. (2007) identified the rat and human CYP450 isoforms, and rat serum esterases that metabolize deltamethrin and esfenvalerate. Differences in the rates of hepatic oxidative metabolism were related to expression levels (abundance) of the individual P450 isoforms rather than their specific activity. 

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