Hydroxylation pyrethroid metabolism

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. 

CYP6D1 of the housefly (Musca domestica) has been found to hydroxylate cyper-methrin and thereby provide a resistance mechanism to this compound and other pyrethroids in this species (Scott et al. 1998 see also Chapter 12). Also, this insect P450 can metabolize plant toxins such as the linear furanocoumarins xanthotoxin and bergapten (Ma et al. 1994). This metabolic capability has been found in the lepi-dopteran Papilio polyxenes (black swallowtail), a species that feeds almost exclusively on plants containing furanocoumarins. 

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... 

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... 

Pyrethroids are poorly absorbed through the skin and are only moderately absorbed in the gastrointestinal tract. Metabolism of deltamethrin occurs rapidly through ester cleavage and hydroxylation. Deltamethrin is eliminated more slowly from adipose tissues than from other sites such as brain or blood. In one case of dermal exposure, absorption was estimated to be 3%. Urinary excretion is the primary route of elimination. 

UGT is a membrane-bound protein with a poorly defined 3-dimensi(Mial structure (Sorich et al. 2006). According to Chang and Benet (2005), the U ax and constants for naphthol glucuronidation by human liver microsomes are 20.2 nmol min mg and 216 pM, respectively. Little if any of the hydroxylated intact pyrethroids are conjugated prior to being eliminated. The importance of the activities of transporters and metabolizing enzymes in the ADME of pyrethroids has yet to be established. Inhibitors of these systems may be used to study their effect on ADME (Lau et al. 2003). 

The Enslein Model in ADMET Predictor supplies and y ax values, respectively, in units of pM and nmol min runoP P450. For user convenience, V ass. is converted into units of nmol min mg microsomal protein (human liver) and into metabolic intrinsic clearance units of pL min mg microsomal protein. The conversion factors were obtained from Inoue et al. (2006). The Enslein Metabolism Module was used to predict and y, values for the hydroxylation of 15 pyrethroids... 

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. 

Develop in vitro metabolic rate constants (Fmax and m) for the CYP-catalyzed hydroxylation of parent pyrethroids (i.e., active pyrethroid isomers, enantiomer pairs), and the carboxylesterase-catalyzed hydrolysis of parent and hydroxylated... 

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