Neurotoxic Insecticides as Antagonists of the GABAA Receptor Function

Chapter 7

Neurotoxic Insecticides as Antagonists of the GABA Receptor Function A

Downloaded by CORNELL UNIV on August 29, 2016 | http://pubs.acs.org Publication Date: November 9, 1987 | doi: 10.1021/bk-1987-0356.ch007

Jeffrey R. Bloomquist, Pamela M. Adams, and David M. Soderlund Department of Entomology, New York State Agricultural Experiment Station, Cornell University, Geneva, NY 14456

Eight cyclodiene insecticides or insecticide metabolites inhibited γ-aminobutyric acid (GABA)-dependent chloride uptake by mouse brain synaptic vesicles with potencies closely related to their acute toxicities. Lindane and deltamethrin also inhibited GABA-stimulated chloride flux, but low potency (lindane) and incomplete stereospecificity (deltamethrin) suggest that the GABA receptor-ionophore complex is not the principal site of action for these compounds. Abamectin, which has been shown to activate chloride channels, failed to stimulate chloride uptake but was a very potent inhibitor of GABAdependent chloride channel activation. These studies illustrate the value of this assay for defining the effects of insecticides on GABA receptor function. The γ-aminobutyric acid (GABA) r e c e p t o r - c h l o r i d e ionophore complex mediates i n h i b i t o r y synaptic neurotransmission i n both vertebrate and invertebrate nervous systems. This complex has been implicated as a s i t e of neurotoxic action for several groups of i n s e c t i c i d e s , i n c l u d ing cyclodienes and l i n d a n e (J_-5_), p y r e t h r o i d s c o n t a i n i n g the acyano-3-phenoxybenzyl moiety (_67_), the avermectins (8-11) » and a new series of b i c y c l i c orthobenzoate esters related to the cage c o n v u l sant t^-butylbicyclophosphorothionate (TBPS) (I2>JL3). Most of the evidence for insecticide e f f e c t s on t h i s t a r g e t has been obtained from p h y s i o l o g i c a l s t u d i e s at peripheral synapses i n invertebrates (_7,8^_Π) or from radioligand binding studies using s u b c e l l u l a r f r a c tions of mammalian brain or insect ventral nerve cord homogenates ^2_6,J9,JLO, 13). Physiological methods are able to provide evidence f o r insecticide-dependent modifications of GABA receptor-ionophore func t i o n , but a p p l i c a t i o n of these methods to i d e n t i f i e d G A B A e r g i c synapses i n central nervous system (CNS) preparations i s t e c h n i c a l l y d i f f i c u l t . Radioligand displacement s t u d i e s provide evidence f o r binding interactions between insecticides and this target i n the CNS, but they are unable to demonstrate the consequences of b i n d i n g i n terms of a l t e r e d r e c e p t o r f u n c t i o n . Thus, a d d i t i o n a l methods to define the consequences of insecticide-GABA receptor i n t e r a c t i o n s i n the CNS are c l e a r l y needed. 9

0097-6156/87/0356-0097$06.00/0 © 1987 American Chemical Society Hollingworth and Green; Sites of Action for Neurotoxic Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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Recently, Harris and A l l a n (_14) described a method f o r s t u d y i n g the c o u p l i n g of GABA r e c e p t o r b i n d i n g s i t e s t o ^ t h e i r a s s o c i a t e d chloride ionophore by measuring GABA-stimulated CI uptake i n t o s y n a p t i c v e s i c l e s prepared from mouse brain. Preliminary studies i n this laboratory (15) and elsewhere (1_6) demonstrated the u t i l i t y of t h i s system to d e f i n e the e f f e c t s of i n s e c t i c i d e s on GABA receptorionophore f u n c t i o n . T h i s paper summarizes f u r t h e r use of these methods to d e f i n e the effects of cyclodienes, lindane, pyrethroids, and avermectins at the GABA receptor-ionophore complex and to c o r r e l a t e i n v i t r o effects with the neurotoxic actions of these compounds i n vivo.


Methods Chemicals. Abamectin (a mixture of 80% avermectin Β and 20% a v e r m e c t i n Β ) was provided by Dr. J . M o l l e t , Merclc Sharp & Dohme Research L a b o r a t o r i e s , Three B r i d g e s , NJ. The sources of other compounds used i n these assays are given elsewhere (15,17). fe

Chloride f l u x assay. Synaptic v e s i c l e s were prepared from b r a i n s of male I C R ^ g i c e (20-30 g; Blue Spruce Farms, Altamont, NY) ( 15). Assays of CI uptake involved preincubation (10-20 min) of v e s i c l e s with c a r r i e r s o l v e n t (ethanol or acetone, 0.5-1 y l ) or i n s e c t i c i d e , followed by incubation (4 sec) with C l " with or without GABA or added i n s e c t i c i d e s and i s o l a t i o n of l a b e l l e d v e s i c l e s by rapid vacuum f i l t r a t i o n . Detailed descriptions of the assay are p u b l i s h e d e l s e where (1_5,L7). Abamectin stock solutions were prepared i n absolute ethanol i n s i l a n i z e d glass v i a l s . Abamectin i n ethanol (1 y l ) was added to give concentrations of 3 nM-3 μΜ i n a f i n a l volume of 200 y l of v e s i c l e suspension during preincubation or 3 μΜ i n a f i n a l volume of 200 y l of C l " uptake medium. Determination of signs of i n t o x i c a t i o n . Muscimol i n p h y s i o l o g i c a l s a l i n e and abamectin i n t r i e t h y l e n e g l y c o l dimethyl ether were ad m i n i s t e r e d to mice by i n t r a p e r i t o n e a l (IP) i n j e c t i o n (50 y l o f v e h i c l e ) or i n t r a c e r e b r a l i n j e c t i o n as d e s c r i b e d by Lawrence and Casida (18; 1-3 y l of v e h i c l e ) . Animals were observed a f t e r dosing for the appearance of excitatory or depressant signs of i n t o x i c a t i o n . Effects of GABA Agonists and Antagonists Harris and A l l a n (j_4) showed a concentration-dependent stimulation of c h l o r i d e uptake by GABA i n mouse b r a i n p r e p a r a t i o n s and the ap p r o p r i a t e s t i m u l a t i o n or i n h i b i t i o n of t h i s uptake by drugs and toxins known to a c t at the GABA^ r e c e p t o r . We confirmed a s i g n i f i c a n t and h i g h l y r e p r o d u c i b l e stimulation of chloride uptake by 100 yM GABA (_15) and a s i m i l a r e f f e c t of 100 y M muscimol, a GABA a g o n i s t (_^9 ). GABA-stimulated c h l o r i d e f l u x was i n h i b i t e d by picrotoxinin ( I - 11.2 yM; 15) and TBPS ( I « 1.3 yM; 17), which are e s t a b l i s h e d physiological antagonists of GABA-gated chloride conduc tance. These findings demonstrate that the c h l o r i d e f l u x assay i s s u i t a b l e f o r i n v e s t i g a t i n g the i n h i b i t o r y GABA^ receptor and i t s associated chloride ionophore as a functional u n i t . Q

Hollingworth and Green; Sites of Action for Neurotoxic Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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Effects of Polychlorocycloalkane Insecticides Cyclodiene i n s e c t i c i d e s or t h e i r n e u r o t o x i c m e t a b o l i t e s have been found to be potent i n h i b i t o r s of [ H]dihydropicrotoxinin (DHPTX) or [ S]TBPS binding to membranes from mammalian and insect CNS preparat i o n s (.2-J5) · We e v a l u a t e d e i g h t c y c l o d i e n e i n s e c t i c i d e s or i n s e c t i c i d e metabolites as i n h i b i t o r s of GABA-dependent chloride f l u x i n mouse brain v e s i c u l a r preparations (17)· 12-Ketoendrin, the most toxic compound i n this s e r i e s , was a l s o the most potent i n h i b i t o r ( I = 0.86 yM; F i g u r e 1). I n h i b i t o r y potency decreased f o r other compounds i n the following order: isobenzan; e n d r i n ; d i e l d r i n ; hept a c h l o r epoxide; a l d r i n ; h e p t a c h l o r (_17; see F i g u r e 1). Aldrin t r a n s - d i o l , the l e a s t e f f e c t i v e compound i n the s e r i e s , produced approximately 25% i n h i b i t i o n at 100 yM. We found a s i g n i f i c a n t l i n e a r correlation between potency i n the c h l o r i d e f l u x assay and acute o r a l t o x i c i t y f o r the seven most potent cyclodienes (Figure 2A). For these seven compounds, potency i n the c h l o r i d e f l u x assay wa^ a l s o h i g h l y c o r r e l a t e d w i t h potency i n the i n h i b i t i o n of [ S]TBPS binding to rat b r a i n membranes ( F i g u r e 3 ) . The t e n f o l d lower s e n s i t i v i t y of the c h l o r i d e uptake assay may r e f l e c t the e f f e c t s of endogenous GABA on the c y c l o d i e n e - c h l o r i d e i o n o p h o r e i n t e r a c t i o n during preincubation. U n l i k e the v e s i c l e s used f o r chloride uptake, the membranes used i n b i n d i n g s t u d i e s are extens i v e l y washed to remove endogenous GABA (4-6,20), which antagonizes [ S]TBPS binding (20). These results show that the i n t e r a c t i o n of c y c l o d i e n e i n s e c t i c i d e s with the TBPS b i n d i n g s i t e on the GABA receptor-ionophore complex i s d i r e c t l y correlated with i n h i b i t i o n of chloride ionophore a c t i v a t i o n , which i n turn appears to be a c r i t i c a l event i n determining acute t o x i c i t y i n this s e r i e s . Thus, c h l o r i d e f l u x s t u d i e s c o n f i r m and s t r e n g t h e n the h y p o t h e s i s that the GABA receptor-ionophore complex i s the p r i n c i p a l s i t e of a c t i o n of cyclodiene i n s e c t i c i d e s . Recent studies have grouped lindane with the cyclodienes on the b a s i s jaf i t s potent and s t e r e o s p e c i f i c i n h i b i t i o n of [H]DHPTX (2,3) and [ S]TBPS (4^5) binding. However, the quantitative c o r r e l a t i o n s between potency i n the chloride f l u x assay, potency i n the [ S]TBPS b i n d i n g assay, and acute t o x i c i t y t h a t were o b s e r v e d f o r the c y c l o d i e n e s do not extend to lindane. Lindane was a very weak i n h i b i t o r of chloride uptake ( I C Q 1 JjO* Inclusion of the data p o i n t f o r l i n d a n e i n the p l o t c o r r e l a t i n g potency i n the chloride uptake assay with acute t o x i c i t y ( F i g u r e 2B) c l e a r l y shows that l i n d a n e cannot be grouped with the cyclodienes i n relating i n v i t r o potency with i n t o x i c a t i o n . The f a i l u r e of lindane to f i t t h i s c o r r e l a t i o n may simply r e f l e c t the divergent pharmacokinetic behavior of hexachlorocyclohexane isomers and cyclodienes. However, lindane also does not f i t the strong c o r r e l a t i o n between the two i n v i t r o potency indices observed f o r the cyclodienes (Figure 3). In t h i s r e l a t i o n s h i p , l i n d a n e i s 5 0 - f o l d l e s s potent as an i n h i b i t o r of chloride untake than would be predicted from i t s potency as an i n h i b i t o r of [ S]TBPS b i n d i n g . These data suggest that l i n d a n e , u n l i k e the cyclodienes, can bind s t e r e o s p e c i f i c a l l y with h i g h a f f i n i t y to the TBPS r e c o g n i t i o n s i t e without s i g n i f i c a n t l y a l t e r i n g c h l o r i d e ionophore function. We conclude from these studies that s i t e s other


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[Cyclodiene], μΜ Figure 1. Concentration-dependent i n h i b i t i o n of GABA-stimulated c h l o r i d e f l u x i n mouse b r a i n v e s i c l e s by f o u r c y c l o d i e n e s . Redrawn from data i n Ref. 15 (endrin, d i e l d r i n ) and Ref. 17 (12ketoendrin, a l d r i n ) .

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Figure 2. (A) Correlation by least squares l i n e a r r e g r e s s i o n of i n h i b i t o r y potency i n c h l o r i d e f l u x assays w i t h acute o r a l t o x i c i t y f o r 12-ketoendrin ( 1 ) , isobenzan ( 2 ) , e n d r i n ( 3 ) , d i e l d r i n (4), heptachlor epoxide (5), a l d r i n (6), and heptachlor (7). Redrawn from Ref. 17. (B) Relationship of the r e g r e s s i o n of Figure 2A to the data point f o r lindane (8).


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than the GABA receptor-ionophore complex may be involved i n lindane neurotoxicity. The p o l y c h l o r i n a t e d cage compounds mirex and chlordecone were very poor i n h i b i t o r s of GABA-dependent c h l o r i d e uptake, producing l i t t l e or no i n h i b i t i o n at 100 μΜ (J^7). These compounds also f a i l e d to i n h i b i t [ S]TBPS b i n d i n g at c o n c e n t r a t i o n s up to 10 μΜ ( 4 ) . Thus, despite the potent i n h i b i t i o n of [H]DHPTX binding i n cockroach CNS preparation by chlordecone (_3 ), i t appears t h a t these compounds act at s i t e s other than the GABA receptor-ionophore complex i n mam mals.


Effects of Pyrethroid Insecticides Electrophysiological studies have i d e n t i f i e d the voltage-dependent sodium channel of nerve membranes as the p r i n c i p a l s i t e of pyrethroid a c t i o n (2_1). However, p y r e t h r o i d s that c o n t a i n the a - c y a n o - 3 p h e n o x y b e n z y l moiety and produce the CS or ".Type I I " p o i s o n i n g syndrome i n mammals (22) i n h i b i t the binding of [ S]TBPS (6) or the convulsant benzodiazepine [ H]Ro5-4864 (23) to rat brain membranes, thus implicating the GABA r e c e p t o r - i o n o p h o r e complex as a s i t e of a c t i o n f o r these compounds. We explored the e f f e c t s of pyrethroids on GABA receptor-ionophore function i n the chloride f l u x assay u s i n g d e l t a m e t h r i n , i t s nontoxic enantiomer, and NRDC 157 (3-phenoxybenzyl [lR,cis]-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate) as test compounds. Preincubation of membranes with deltamethrin, which gives the CS p o i s o n i n g syndrome, produced concentration-dependent i n h i b i t i o n of GABA-dependent chloride f l u x (Figure 4). I n h i b i t i o n was not complete but reached a maximum of s l i g h t l y more than 50% at high concentra tions. NRDC 157, the non-cyano analog of deltamethrin that produces the Τ or "Type I" poisoning syndrome (_22), was not i n h i b i t o r y i n this assay (Γ7). The enantiomer of deltamethrin, which i s more than 500f o l d l e s s toxic than deltamethrin by intracerebral administration to mice (2A) was also i n h i b i t o r y and approximately ten-fold less potent than d e l t a m e t h r i n ( F i g u r e 4 ) . Thus, the a c t i o n s of p y r e t h r o i d s s t e r e o i s o m e r s i n t h i s system f a i l to e x h i b i t the p r o f o u n d s t e r e o s p e c i f i c i t y observed i n t o x i c i t y determinations and also do not confirm the extent of s t e r e o s p e c i f i c i t y claimed for the i n h i b i t i o n of [ S]TBPS binding by deltamethrin and related compounds (6). Because stereospecif i c i t y i n pyrethroid i n t o x i c a t i o n appears to r e s u l t from the c h i r a l i t y of the pyrethroid receptor s i t e (JJ$,22), pharmacologi cal e f f e c t s lacking this stereospecif i c i t y , such as those shown i n F i g u r e 4, are probably not c r i t i c a l l y involved i n i n t o x i c a t i o n . Our f i n d i n g s t h e r e f o r e tend to r u l e out the GABA r e c e p t o r - i o n o p h o r e complex as a t o x i c o l o g i c a l l y relevant s i t e of pyrethroid action. y

Effects of Abamectin The avermectins have been shown to increase chloride conductance i n invertebrate e l e c t r o p h y s i o l o g i c a l preparations (J3»H>25) modulate the b i n d i n g of s e v e r a l GABA receptor-ionophore ligands (j* ,JL0), but the molecular mechanisms underlying their neurotoxicity remain poorly defined. R e c e n t l y , A b a l i s e_t a l . (JL6) reported an avermectin B. dependent stimulation of chloride uptake i n rat b r a i n v e s i c l e s that a

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I50 for Cl" uptake, μ M Figure 3. C o r r e l a t i o n by l e a s t squares l i n e a r r e g r e s s i o n of i n h i b i t o r y potencies i n [ S]TBPS b i n d i n g assays (4) with i n h i b i t o r y potencies i n c h l o r i d e f l u x assays ( J J > , 12) f o r seven cyclodienes. The data p o i n t f o r lindane i s also shown but not included i n the calculated regression. Redrawn from Ref. 17. 60 •

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was s e n s i t i v e to b i c u c u l l i n e i n h i b i t i o n , thus suggesting a GABAmimetic action for t h i s compound. We explored the action of abamectin i n the mouse brain chloride f l u x assay under several conditions (Figure,5) Abamectin at 3 yM i n e i t h e r the p r e i n c u b a t i o n medium or the C l uptake medium did not stimulate chloride uptake above background l e v e l s , whereas GABA at 100 yM produced a t y p i c a l stimulation of uptake, thereby confirming the v i a b i l i t y of the tissue preparation. Moreover, abamectin at 3 yM i n the p r e i n c u b a t i o n medium completely i n h i b i t e d GABA-dependent stimulation. This antagonistic e f f e c t of abamectin c l e a r l y d i f f e r s from i t s GABA-mimetic a c t i v i t y i n similar experiments with rat brain (JJj). In further experiments, we characterized the e f f e c t of abamect i n c o n c e n t r a t i o n on t h i s i n h i b i t o r y e f f e c t (Figure 6). I n h i b i t i o n of GABA-dependent uptake was barely detectable at 10 nM and extensive at 1 yM. The I f o r abamectin i n this assay i s approximately 100 nM, making this compound almost 9-fold more potent as an i n h i b i t o r than 12-ketoendrin, the most potent cyclodiene (Figure 1). We performed p r e l i m i n a r y s t u d i e s of the s i g n s of abamectin i n t o x i c a t i o n i n mice to determine whether antagonism of GABA-mediated i n h i b i t o r y transmission i n vivo might produce n e u r o e x c i t a t i o n ( 19) · Abamectin administered either IC or IP at j u s t - l e t h a l doses produced an i n i t i a l period of hyperexcitation, h y p e r s e n s i t i v i t y to p h y s i c a l and a u d i t o r y s t i m u l i , i n c r e a s e d locomotor a c t i v i t y , and tremor (IP only). The duration of t h i s p e r i o d v a r i e d with both route of adm i n i s t r a t i o n and dose: excitatory signs were observed for less than an hour at j u s t - l e t h a l IC doses and intermittently for up t o 6 hours at j u s t - l e t h a l IP doses, but these periods were shortened or completely absent at l e t h a l overdoses by both routes of a d m i n i s t r a t i o n . These p r e l i m i n a r y findings agree with our i n v i t r o studies and suggest that abamectin may produce both neuroexcitatory e f f e c t s , perhaps by antagonism of GABA-mediated i n h i b i t i o n , and depressant e f f e c t s , perhaps by a c t i v a t i o n of chloride channels. The l a t t e r e f f e c t i s not observed under our i n v i t r o assay conditions but has been documented i n invertebrate nerve preparations (11).


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Conclusions Our studies show that c h l o r i d e f l u x assays u s i n g s y n a p t i c v e s i c l e p r e p a r a t i o n s from CNS homogenates provide unique and valuable i n f o r mation on the a l t e r a t i o n of normal GABA r e c e p t o r - c h l o r i d e ionophore f u n c t i o n by n e u r o t o x i c i n s e c t i c i d e s . Whereas radioligand binding assays define molecular i n t e r a c t i o n s between t o x i c a n t s and t a r g e t s i t e s , f u n c t i o n a l assays provide information on the consequences of binding i n t e r a c t i o n s . The d i v e r g e n t behavior of c y c l o d i e n e s and l i n d a n e i n the binding and chloride f l u x assays i l l u s t r a t e s both the d i f f e r e n t types of information obtained i n each assay and the value of the l a t t e r system i n d e s c r i b i n g toxicant e f f e c t s on target s i t e function. Using the c h l o r i d e f l u x assay as an index of a l t e r e d f u n c t i o n , we have provided strong evidence that the neurotoxic effects of cyclodienes result from i n h i b i t i o n of GABA-gated c h l o r i d e conductance at i n h i b i t o r y synapses. We have also shown that lindane and deltamethrin produce q u a l i t a t i v e l y s i m i l a r e f f e c t s i n v i t r o , but that these e f f e c t s are poorly correlated with i n t o x i c a t i o n events i n vivo. F i n a l l y , we have documented an u n a n t i c i p a t e d a n t a g o n i s t i c effect of abamectin on GABA-dependent chloride uptake.



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[Abamectin], μΜ F i g u r e 5. E f f e c t s of abamectin (AM) at 3 μΜ i n e i t h e r the preincubation or C l uptake medium on basal chloride uptake and at 3 μΜ i n the preincubation medium on uptake stimulated by GABA (100 μ Μ ) . Ethanol (EtOH; 1 μΐ) was the control f o r AM addition to the preincubation medium. Results are means + standard errors of t o t a l c h l o r i d e uptake per mg protein from three experiments using d i f f e r e n t v e s i c l e preparations (26).

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F i g u r e 6. Effect of preincubation with d i f f e r e n t concentrations of abamectin on subsequent c h l o r i d e f l u x s t i m u l a t e d by 100 μΜ GABA. Results are means + standard errors of normalized s p e c i f i c chloride uptake i n three experiments u s i n g d i f f e r e n t v e s i c l e preparations (26).



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To our knowledge, the successful use of this synaptic v e s i c u l a r assay i s l i m i t e d to mammalian CNS p r e p a r a t i o n s (14-17). We have attempted to t r a n s f e r the methodology to s t u d y GABA receptorionophore f u n c t i o n i n subcellular fractions prepared from cockroach (Periplaneta americana) thoracic nerve cords. These s t u d i e s so f a r have provided some evidence for GABA-dependent chloride uptake, but the magnitude of t h i s e f f e c t i s small and h i g h l y v a r i a b l e from p r e p a r a t i o n to p r e p a r a t i o n (26.)· I t i s l i k e l y that the l i m i t i n g constraint i n t h i s e f f o r t i s the i s o l a t i o n of s t a b l e , v i a b l e p o s t s y n a p t i c v e s i c l e s from insect CNS homogenates. The use of novel methods to prepare f u n c t i o n a l synaptosomes from i n s e c t CNS t i s s u e a f t e r many years of f a i l u r e (27^28.) suggests that new methods f o r i s o l a t i o n of mixed p r e s y n a p t i c and p o s t s y n a p t i c v e s i c l e s can be i d e n t i f i e d that are a p p r o p r i a t e to the neuronal a r c h i t e c t u r e of insect ganglia, the size d i s t r i b u t i o n of i n s e c t p o s t s y n a p t i c t e r m i n a l s , and the s u s c e p t i b i l i t y of the r e s u l t i n g v e s i c l e s to physical and osmotic i n s u l t . Recent studies indicating that i n s e c t CNS GABA r e c e p t o r s d i f f e r i n t h e i r pharmacological p r o f i l e from both types of mammalian GABA receptor (29) should provide further stimulus f o r the extension for these methods to insect tissue. Acknowledgments These s t u d i e s were supported by grants from the National Institutes of H e a l t h ( E S 2 1 6 0 ) , t h e N a t i o n a l S c i e n c e F o u n d a t i o n (PCM 8400099/Biological Instrumentation), and Merck Sharp & Dohme Research Laboratories, Inc. We thank M. Eldefrawi for communicating r e s u l t s prior to publication.

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