Pyrethroids metabolism

In addition, three types of lipophilic conjugates have been found in pyrethroid metabolism studies (Fig. 4). They are cholesterol ester (fenvalerate) [15], glyceride (3-PBacid, a common metabolite of several pyrethroids) [16], and bile acid conjugates (fluvalinate) [17]. It is noteworthy that one isomer out of the four chiral isomers of fenvalerate yields a cholesterol ester conjugate from its acid moiety [15]. This chiral-specific formation of the cholesterol ester has been demonstrated to be mediated by transesterification reactions of carboxylesterase(s) in microsomes, not by any of the three known biosynthetic pathways of endogenous cholesterol esters... 

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. 

No explicit sex-related difference in ester cleavage of pyrethroids was reported in pyrethroid metabolism in mammals. 

Lertkiatmongkol P, Jenwitheesuk E, Rongnoparut P (2011) Homology modeling of mosquito cytochrome P450 enzymes involved in pyrethroid metabolism insights into differences in substrate selectivity. BMC Res Notes 6 321... 

The mechanisms by which pyrethroids alone are toxic are complex and become more complicated when they are co-formulated with piperonyl butoxide, an organ-ophosphorus insecticide, or both, as these compounds inhibit pyrethroid metabolism. The main effects of p3rethroids are on sodium and chloride channels. As a result, excitable (nerve and muscle) cells are the principal targets of pyrethroid toxicity, which is manifested as disordered function rather than structural damage. In that way, the major toxic effect of dermal exposure is paresthesia, supposable also due to hyperactivity of cutaneous sensory nerve fibers [12]. 

Analysis of human CE by Northern blot shows a single band of approximately 2.1 kilobases (kb) (Riddles et al. 1991), and three bands of approximately 2-, 3-, and 4.2-kb occurring with hCE-2 (Schwer et al. 1997). The intensities of the 2.1-kb band were liver 3> heart > stomach > testis > kidney = spleen > colon > other tissues. For hCE-2, the 2-kb band was located in liver > colon > small intestine > heart, the 3-kb band in liver > small intestine > colon > heart, and the 4.2-kb band in brain, testis, and kidney only. Analysis of substrate structure versus efficiency for ester (pyrethroid substrates) revealed that the two CEs recognize different structural features of the substrate (i.e., acid, alcohol, etc.). The catalytic mechanism involves the formation of an acyl-enzyme on an active serine. While earlier studies of pyrethroid metabolism were primarily performed in rodents, knowledge of the substrate structure-activity relationships and the tissue distribution of hCEs are critical for predicting the metabolism and pharmacokinetics of pesticides in humans. Wheelock et al. (2003) used a chiral mixture of the fluorescent substrate cyclopro-panecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-, cyano(6-methoxy-2-naphthalenyl)methyl ester (CAS No. 395645-12-2) to study the hydrolytic activity of human liver microsomes. Microsomal activity against this substrate was considered to be low (average value of ten samples 2.04 0.68 nmol min mg ), when compared to p-nitrophenyl acetate (CAS No. 830-03-5) at 3,700 2,100 mg ... 

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. 

Clark JM, Brooks MW (1989) Role of ion channels and intrateiminal calcium homeostasis in the action of deltamethrin at presynaptic nerve terminals. Biochem Pharmacol 38 2233-2245 Class TJ, Ando T, Casida JE (1990) Pyrethroid metabolism microsomal oxidase metabolites of (S)-bioallethrin and the six natural pyrethrins. J Agric Food Chem 38 529-537 Cole LM, Ruzo LO, Wood EJ, Casida JE (1982) Pyrethroid metabolism comparative fate in rats of tralomethrin, tralocythrin, deltamethrin, and (IR, alphaS)-cw-cypermethrin. J Agric Food Chem 30 631-636... 

Many pesticides are not as novel as they may seem. Some, such as the pyre-throid and neonicotinoid insecticides, are modeled on natural insecticides. Synthetic pyrethroids are related to the natural pyrethrins (see Chapter 12), whereas the neo-nicotinoids share structural features with nicotine. In both cases, the synthetic compounds have the same mode of action as the natural products they resemble. Also, the synthetic pyrethroids are subject to similar mechanisms of metabolic detoxication as natural pyrethrins (Chapter 12). More widely, many detoxication mechanisms are relatively nonspecific, operating against a wide range of compounds that... 

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. 

The organophosphorons insecticides dimethoate and diazinon are mnch more toxic to insects (e.g., housefly) than they are to the rat or other mammals. A major factor responsible for this is rapid detoxication of the active oxon forms of these insecticides by A-esterases of mammals. Insects in general appear to have no A-esterase activity or, at best, low A-esterase activity (some earlier stndies confnsed A-esterase activity with B-esterase activity) (Walker 1994b). Diazinon also shows marked selectivity between birds and mammals, which has been explained on the gronnds of rapid detoxication by A-esterase in mammals, an activity that is absent from the blood of most species of birds (see Section 23.23). The related OP insecticides pirimiphos methyl and pirimiphos ethyl show similar selectivity between birds and mammals. Pyrethroid insecticides are highly selective between insects and mammals, and this has been attributed to faster metabolic detoxication by mammals and greater sensitivity of target (Na+ channel) in insects. 

Resistance mechanisms associated with changes in toxicokinetics are predominately cases of enhanced metabolic detoxication. With readily biodegradable insecticides such as pyrethroids and carbamates, enhanced detoxication by P450-based monooxygenase is a common resistance mechanism (see Table 4.3). 

The metabolism of permethrin will be taken more generally as an example of the metabolism of pyrethroids (Figure 12.2). The two types of primary metabolic attack are by microsomal monooxygenases and esterases. Monooxygenase attack involves... 

Tyler, C.R., Beresford, N., and van der Woning, M. et al. (2000). Metabolism and environmental degradation of pyrethroid insecticides produce compounds with endocrine activities. Environmental Toxicology and Chemistry 19, 801-809. 

Pyrethroid insecticides are rapidly metabolized to their inactive acids and alcohol components, which are excreted primarily in urine. A small portion of the absorbed compounds is excreted unchanged. Occupational exposure to pyrethroid insecticides can be assessed by measuring intact compounds or their metabolites in urine. Biological indicators of internal dose in exposed subjects are reported in Table 7. Due to their rapid metabolism, determination of blood concentrations can only be used to reveal recent high-level exposures. 

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