Substrate Specificity of Mouse-Liver Microsomal ... - ACS Publications

15 Substrate Specificity of Mouse-Liver Microsomal Enzymes in Pyrethroid Metabolism DAVID M. SODERLUND and JOHN E. CASIDA 1

Pesticide Chemistry and Toxicology Laboratory, Department of Entomological Sciences, University of California, Berkeley, Calif. 94720

Rapid detoxification contributes to the low acute and chronic toxicity to mammals of the pyrethrins and other chrysanthemates ( 1 , 2 ) . Increased insecticidal potency in the newer synthetic pyrethroids has been achieved by replacing some of the biodegradable groupings by substituent s that retain overall insecticidal configurations but are more refractory to metabolism (3). Currently important pyrethroids include 9 acid moieties [A-I; shown as 1R,trans (A-F) or most insecticidal isomer (G, I] and 9 alcohol moieties [ a - i ; the most insecticidal isomer of a-c and is shown] as follows (Figure l ) : h

acid

A: C: D: E:

R R R R

= = = =

moieties

CHF ' CI Br H alcohol

I

H

moieties

Figure 1


in

cyclo­

Figure

relationship

3-phenoxybenzyl

(R =Cl

molecular

chain at

CH^ >

esters

Br).

is

164

SYNTHETIC

yy^LioR >

^^^^ΐΓ^)

=

HYDROLYSIS

Ρ

^JLXor

R

PYRETHROIDS

-y^ioR * RHXAOR

>

R' = CI > F > CH> Br 326 300 166 128 40 [1RS]

R all substituents /=

3

1500 >1500 >1000 >1500

1°

tt

50

trans

Τ.ΤΊ

Toxicity

no t r a n s / c i s

with

and

alcohol

Acid

Intraperitoneal

^trans-ester

[lR]

available;

[ l R , c i s ] - e s t e r

data

S-3206 s-5602 [ R S 3

[1RS]

lk9

NRDC

Cyanophenothrin

Allethrin

Ethanoresmethrin

[1R]

Phenothrin

^ 0

Mouse

configuration

and

I.

Resmethrin

acid

Compound

Table

I—»

3

ο

η

o'

15.

SODERLUND A N D CASIDA

Table

II.

Resmethrin

Ester

Enzyme

Metabolites

and -Permethrin, Acid and

Compound Resmethrin Permethrin

Substrate

of

Specificity in Pyrethroids

[lR,trans]-

Rat

in

[lR,cis]-

vivo

Ester

alcohol

metabolites,^

moieties

trans

Af

and

171