16 Stereospecificity of Pyrethroid Metabolism in Mammals DAVID M. SODERLUND and JOHN E. CASIDA 1
Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720
For high insecticidal activity, pyrethroids must have a precise steric relationship between an unsaturated center in the alcohol moiety and the gem-dimethyl group or an equivalent substituent in the acid moiety ( l ) . This generally requires a 1R configuration in the cyclopropanecarboxylic acid and an α-S configuration in the alcohol. Inversions at these optical centers drastically alter the potency without greatly changing the physical properties. Pyrethroid insecticides are commonly used as isomeric mixtures or, i f a single isomer is involved, the residues sometimes undergo photochemical isomerization and epimerization. Metabolic studies on isomeric mixtures may not reflect the rates and sites of attack on the most bioactive components i f metabolic stereoselectivity i s encountered. It is therefore important to define the stereospecificity in metabolism of the optical antipodes and i t s relevance in pyre throid toxicology and residue persistence. We previously reviewed the influence of trans- and c i s substituents on the metabolism of cyclopropanecarboxylates (2-4). This report considers the stereoselectivity in in vitro and in vivo mammalian metabolism of various isomers of resmethrin, permethrin, S-5439 and S-5602 (Figure l ) .
resmethrin
permethrin Figure 1.
S-5439 (X H) S-5602 (X = CN) S
Structures of compounds examined
Present address: Insecticides and Fungicides Department, Rothamsted Experimental Station, Harpenden, Hertfordshire, AL5 2JQ, England. 1
173
174
SYNTHETIC
Resmethrin Methyl
and Site
either
l i v e r
microsomes
trans-
they
the
[I S , t r a n s ] - i s omer
ase
hydrolyze
i s reflected plus
Isobutenyl
(Figure
(Table
o f
with
i ) .
the greater
preference
varies
t h e [ l R ] - a n d [is]-isomers a t essentially
[lR,trans]-resmethrin in
oxidase)
Site groups
oxidize
or cis-resmethrin
but rate
f o rHydroxylation o f
Groups
Mouse of
Preference
PYRETHROIDS
This
t h e same
1.7-times
difference
faster in
rates than
hydrolysis
overall biodegradability
(ester-
[lR,trans]-resmethrin. f o rhydroxylation
both
o f the isobutenyl
t h e chrysanthemate
isomer
and
methyl
species
2).
trans
r 53 m 83'*
OR
m 85
m 95' •Preferred hydroxylation site, ratinvivo. Pesticide Biochemistry and Physiology Figure 2. Stereoselectivity in hydroxylation of isobutenyl methyl groups of resmethrin isomers by mouse (m) and rat (r) microsomes (R = 5benzyl-3-furylmethyl) (5). The percent metabolism at an indicated methyl group is relative to the sum for both methyl groups calculated by summating the identified acid-moiety metabolites.
With
t h e mouse
group
isomers with
enzyme,
while
thecis(Z)
site
tions. vitro
Where
preference In vivo
results
position
butonly data
from
i s reversed
data
o f thetrans(E)
the [lR,trans]-
methyl
the [lS,cis]-isomer
[lR,cis]-isomer. the
hydroxylation
i s preferred with both
f o rrats
i s strongly
slightly
preferred
t h e r a t enzyme
from
that
preferred with the
a r e available,
w i t h mouse
(6) a r e consistent
f o r the [lR,cis]-isomer
methyl
and [IS,trans]-
with
preparat h e in
b u tn o t f o r t h e [ l R , t r a n s ] -
isomer. It
h a sbeen
reaction is
most
result
occurs
proposed within
important from
with
formation
tion
o f t h emethylene
from
other
undefined
(£) that
the series
an oxidative o f resmethrin
[lS,cis]-resmethrin. o f unstable group
cleavage
isomers a n d
This
hydroxylated
adjacent
mechanisms.
ester
cleavage
esters
t o theester
may
by oxida-
function or
