Metabolism

In mammals and birds, pyrethroids augment the electrical activity in the brain, spinal column and peripheral neurons which underlie the induced paresthesia, convulsions, and tremors.38 The low toxicity of pyrethroids is attributed to their rapid metabolism in the blood and liver, with more than 90% of pyrethroids being excreted as metabolites in urine within 24 hours after exposure.80 82 Indeed, although extensively used, there are relatively few reports of human, domestic animal or wild animal pyrethroid poisonings.83,84

Cytochrome P450s are extremely important in the metabolism of xenobiotics and endogenous compounds. Cytochrome P450s can metabolize a large number of substrates because they exist in numerous different isoforms and they have several functional roles, including growth, development and metabolism of xenobiotics. The two types of primary metabolic enzymes involved in the detoxification of pyrethroids are microsomal monooxygenases and esterases. The detoxification of pyrethrins and pyrethroid insecticides is primarily through oxidative metabolism by CYP, which yields metabolites with hydroxyl groups substituted in both the acidic and basic moieties.85 The presence of a cis-substituted acid moiety and a secondary alcohol moiety indicates that hydrolytic metabolism would be limited, and subsequent studies in mammals have found hydrolysis to be minimal.86 The metabolic pathway of cis- and trans-permethrin is displayed in Figure 3.3 and shows the different CYP involved in the metabolism of pyrethroids. The initial biotransformation of pyrethroids is through attack by either esterases at the central ester bond, or by CYP-dependent monooxygenases at one or more of the acid or alcohol moieties, and this generally achieves detoxification of the compound (see Figure 3.3).

Cyp Metabolism
Figure 3.3 Metabolism of permethrin in mammals. Abbreviation CYP: cytochrome P450.

CYPs are not, however, involved in the hydrolysis or in the oxidation of the trans-isomers of pyrethroids to phenoxybenzyl alcohol and phenoxybenzoic acid, the main forms of pyrethroids that are excreted (see Figure 3.3).87 The human alcohol and aldehyde dehydrogenases are the enzymes involved in the oxidation of phenoxybenzyl alcohol to phenoxybenzoic acid (see Figure 3.3).87

For type I pyrethroids, following ester cleavage, the primary alcohol moieties undergo further oxidation via the aldehyde to carboxylic acids. However, type II alcohols lose the cyanide non-enzymatically to form the aldehyde.43 The principal sites of oxidation for pyrethrins I in rats are the terminal double bond and the trans methyl group of the isobutenyl substituent of the acid moiety, which undergoes sequential oxidation to a carboxylic acid.88 In mammals, as in insects, the cis-isomers are generally more toxic than the corresponding trans-isomers. This phenomenon may be because the liver fractions are poor at metabolizing cis-isomers, while the trans-isomers are readily metabolized by esterases.87 The ci's-isomers are also less readily absorbed by the stomach hence limiting their toxicity.37 For reference, technical-grade mixtures of permethrin contain 30% of cis-isomer, while formulations contain about 35%.

Pyrethroids are metabolized predominantly by esterases. The first stage involves cleavage of the ester bond, generating 3-phenoxybenzaldehyde, 3-phen-oxybenzoic acid, and (2,2-dichlorovinyl)-3,3-dimethylcyclopropanecarboxylic acid as major metabolites (see Figure 3.3).89 The major metabolites detected in the urine of mammals (see Figure 3.3) are 3-phenoxybenzoic acid (3PBA; the product of the oxidation of the hydrolytic product of many of pyrethroids), 4-fluoro-3-phenoxybenzoic acid (4F3PBA; a metabolite of the fluorine-substituted pyrethroid insecticides), and cis- and trans-(2,2-dichlorovinyl)-3,3-dimethylcy-clopropane-1-carboxylic acid (cis- and trans-DCCA; metabolites of chlorinated pyrethroids, such as permethrin, cypermethrin and cyfluthrin).80,82,90

There are also specific metabolites for certain pyrethroids. For example, cis-(2,2-dibromovinyl)-3,3-dimethylcyclopropane-1-carboxylic acid (DBCA) is the main metabolite of deltamethrin.90 The ratio of trans: cis DCCA can be used to determine the exposure pathway via dermal and oral routes.91 Other, more minor, metabolites include those resulting from hydroxylation at the acidic gem dimethyl group and at the phenoxy group of the alcohol and from oxidation, which results in carboxylic acids and phenols.92 Once these oxidations occur, the resulting carboxylic acids and phenols may be conjugated by a variety of enzymes, and are subsequently excreted as either free metabolites or conjugated with sugars or amino acids which are rapidly excreted.

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