Carboxylesterase kinetic parameters

Age-related differences in kinetic parameters of detoxification can partially explain the increased sensitivity of the young to acute exposure to chlorpyrifos and other OPs (Mortensen et ai, 1996 Moser et ai, 1998 Padilla et ai, 2000, 2004). Thus, in vitro assays show that differences in vivo are not due to intrinsic differences in sensitivity of the target enzyme (Mortensen el ai, 1998). Furthermore, differences in liver microsomal metabolism, which mediates activation and/or inactivation of some pesticides, do not adequately explain the increased sensitivity (Benke and Murphy, 1975 Brodeur and DuBoks, 1%7). Differences in detoxification pathways correlate better with age sensitivity. B-esterases (e.g., carboxylesterases) and A-esterase.s bind to and/or hydrolyze, and thus detoxify, some cholinesterase-inhibiting pesticides (Jokanovic et al., 1996 Maxwell, 1992). These pathways are much less well developed in the young, and maturation of these systems tracks the decreasing sensitivity to acute exposure to chlorpyrifos and other OPs (Attcrberry el ai, 1997 Benke and Murphy, 1975 Brodeur and DuBois, 1967 Chanda et ai, 1997, 2002 Mendoza, 1976 Mortensen et ai, 1996, 1998 ... 

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. 

Human intestinal microsomes effectively hydrolyzed frans-permethrin however, bioresmethrin, and deltamethrin were not metabolized in the intestine to any appreciable extent. Human hepatic microsomes and cytosol contained both hCE-1 and hCE-2 when examined by native PAGE (polyacrylamide gel electrophoresis) human intestine contained only hCE-2. Table 8 gives the kinetic parameters obtained by Crow et al. (2(X)7) with tranr-permethrin and liver and intestinal carboxylesterases. 

Table 8 Kinetic parameters of trani-permethiin hydrolysis catalyzed by human and rat hepatic subcellular fractions (microsomes and cytosols) and intestinal carboxylesterases...

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

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