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and metabolite 5 is an acid. The oxidative metabolites 1 and 2 are also subject to ester-
atic hydrolysis. Hydrolysis of oxidative metabolite 1 yields again the base, metabo-
lite 4, whereas hydrolysis of oxidative metabolite 2 yields again the acid, metabolite
5. In addition to these, oxidative metabolite 1 yields the hydroxy base, metabolite 6,
whereas oxidative metabolite 2 yields the hydroxy acid, metabolite 3. Thus, taken
together, the esteratic hydrolysis of metabolites 1 and 2 yields, on the one hand, the
same two metabolites that arise from the hydrolysis of permethrin itself and, addition-
ally, two further metabolites (3 and 6) that contain hydroxyl groups that were intro-
duced by oxidative attack upon the parent compound. In summary, metabolites 4 and
5 are the products of esteratic hydrolysis of permethrin; metabolite 4 is also generated
by the hydrolysis of metabolite 1 and metabolite 6 by the hydrolysis of metabolite
2. Metabolites 3 and 6 contain additional hydroxy groups introduced by oxidative
attack. The hydroxyl groups are then available for conjugation with glucuronide, sul-
fate, peptide, etc., depending on species. In both insects and vertebrates the excreted
products are mainly conjugates.
There has been some controversy over the relative importance of oxidation and
esteratic hydrolysis in primary metabolic attack. The strong potentiation of toxicity
of certain pyrethroids to insects by piperonyl butoxide (PBO) and other P450 inhibi-
tors (see Chapter 2, Section 2.5) suggests the dominance of oxidation over hydroly-
sis as a detoxication mechanism. However, the interpretation of metabolic studies has
sometimes been complicated by the shortage, even the apparent absence, of primary
oxidative metabolites such as those shown in Figure 12.2. One problem has been iden-
tification and quantification of conjugates that can be rapidly formed from the various
metabolites containing hydroxy groups, in both in vivo and in vitro studies on insects.
When trying to elucidate the metabolic regulation of toxicity, a difficulty had been
establishing the metabolic pathways by which hydroxylated metabolites such as com-
pounds 3 and 6 were formed. Did hydroxylation occur before or after hydrolytic cleav-
age of the ester bond? In most cases, available evidence strongly suggests that oxidation
predominates over hydrolysis as a primary mode of metabolic attack. In insects, the
marked synergistic action of P450 inhibitors such as PBO and ergosterol biosynthesis
inhibitors (EBIs) (see Chapter 2, Section 2.6) is not consistent with esterase attack, the
dominant mechanism of primary metabolism of pyrethroids. Further, the products of
esteratic cleavage are strongly polar in character and are hardly ideal substrates for the
hydrophobic active centers of cytochrome P450s. It should also be mentioned that the
primary products of oxidative attack are more polar than the original insecticides, and
are likely, on that account, to be better substrates for esterase attack (cf. OP hydrolysis,
Chapter 10). Such a mechanism can explain an observation made by several workers
studying microsomal metabolism of pyrethroids—that switching on P450 oxidation by
addition of NADPH can increase the rate of hydrolysis (Lee et al. 1989).
12.4 enVIronmentaL fate of PyretHroIdS
Pyrethroids are extensively used in agriculture, so agricultural land is often con-
taminated by them. They can also reach field margins and hedgerows through spray
drift. Because of their high toxicity to aquatic organisms, precautions are taken to
prevent their entering surface waters, which can be a consequence of spray drift or
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