Bound and Conjugated Pesticide Residues

6 Sulfate Ester Conjugates—Their Synthesis, Purification, Hydrolysis, and Chemical Spectral Properties G. D. PAULSON

Downloaded by UNIV OF LEEDS on June 18, 2016 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0029.ch006

Metabolism and Radiation Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Fargo, N. Dak. 58102

Since the early report that the dog readily metabolizes phenol to phenyl sulfate (1), a large body of information has been developed about sulfate ester conjugation. Sulfoconjugates are a very diverse and widespread group of compounds that are found in microorganisms, plants (2), Insect (3-5), mammals, birds, reptiles, amphibia, arthropods, and mollusks (6). Dodgson and Rose (7) have classified these compounds in the following way: 1) compounds with P-O-SO- linkages; 2) compounds with C-O-SO3" linkages; 3) compounds with N-SO3- linkages; 4) compounds with N-O-SO- linkages; and 5) compounds with S-SO3- linkages. This review is restricted primarily to compounds with the C-O-SO3linkage, and particularly to aryl sulfates because these are most commonly encountered by the pesticide chemist and have been most extensively investigated. Some aspects of compounds with the P-O-SO- and N-O-SO- linkages will be discussed as they apply to xenobiotic metabolism. 3

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Biosynthesis and Metabolic Fate The early studies by DeMeio (8), DeMeio and Tkacz (9), DeMeio et al. (10), DeMeio et al. (11), Bernstein and McGilvery (12, 13), Segal (14), and others demonstrated that phenols were converted to aryl sulfates by the soluble fraction of rat liver homogenates when incubated with sulfate ions, ATP, and Mg ions. Bernstein and McGilvery (12, 13) and Segal (14) discovered that an active sulfate was formed from ATP and sulfate ion and that the active sulfate reacted with a phenol to give phenyl sulfate. Robbins and Lipmann (15-17) showed that the active sulfate was adenosine-3'-phosphate-S'-phosphosulfate (PAPS), and that two enzymes were involved in the formation of PAPS (15, 16). The first enzyme, ATP-sulfurylase (ATP:sulfate adenyItransferase, 2.7.7.4) catalyzes the reaction of ATP andSO42-ion to give adenosine-5'-phosphosulfate (APS) and pyrophosphate, and the second enzyme APS-kinase (ATP:adenyl sulfate 3'-phosphotransferase, 2.7.1.25) catalyzes the phosphorylation of APS to give PAPS. Baddiley et al. (18, 19) 2+

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confirmed t h e s t r u c t u r e o f both APS and PAPS by s y n t h e s i s . More d e t a i l e d d i s c u s s i o n s o f these and r e l a t e d s t u d i e s are a v a i l a b l e (7, 20-24). The thermodynamically unfavorable formation o f APS (AF • +11 kCal) from ATP and s u l f a t e i s d r i v e n by the h y d r o l y s i s o f pyrophosphate and by t h e r a p i d u t i l i z a t i o n o f APS by APS-kinase (7, 2£, 22). A T P - s u l f u r y l a s e p u r i f i e d from yeast r e q u i r e s M g i o n and i t s pH optimum i s 7.5-9.0. However, Dodgson and Rose (7) d i s cussed species d i f f e r e n c e s and s t r e s s e d the importance o f s e v e r a l v a r i a b l e s when assaying f o r the s u l f a t e a c t i v a t i n g systems i n other p r e p a r a t i o n s . Roy (20, 21) reviewed the methods a v a i l a b l e f o r assay o f A T P - s u l f u r y l a s e a c t i v i t y , i n h i b i t o r s o f t h i s enzyme, and s t u d i e s on p u r i f i c a t i o n o f t h i s enzyme. The conversion o f APS t o PAPS by the APS kinase i s o l a t e d from yeast i s e s s e n t i a l l y i r r e v e r s i b l e (AF • -5 Kcal) and r e q u i r e s M g i o n ; t h e optimum pH f o r t h i s enzyme i s 8.5-9.0 (17). There i s apparently no d e t a i l e d i n f o r m a t i o n on t h i s enzyme i n animal s y s tems although i t i s presumed t o be present i n a l l t i s s u e s t h a t form PAPS (21). Assay techniques and other s t u d i e s on t h i s enzyme, as w e l l as t h e p r o p e r t i e s o f APS and PAPS, have been reviewed by Roy (20, 21) and Dodgson and Rose (7). Recently, Wong (25) r e ported a new method f o r measuring the a c t i v i t y o f the enzymes that generate PAPS and o f the t r a n s f e r a s e enzymes; i t was p o s t u l a t e d that ATP acts as an a l i o s t e r i c m o d i f i e r o f one o f the enzymes r e s p o n s i b l e f o r t h e s y n t h e s i s o f PAPS. The a b i l i t y t o s y n t h e s i z e PAPS (an e n e r g e t i c a l l y expensive process f o r t h e organism) i s common t o a wide v a r i e t y o f p l a n t s , animals, and microorganisms. The involvement o f PAPS i n s u l f a t e r e d u c t i o n , s u l f a t e t r a n s p o r t , s u l f o c o n j u g a t l o n o f carbohydrates, and g l y c o l i p i d s and i n many other d i v e r s e metabolic r e a c t i o n s ( 7 , 20, 21) i s beyond t h e scope o f t h i s review. Rather, t h i s d i s cussion w i l l be r e s t r i c t e d p r i m a r i l y t o t h e involvement o f PAPS and s u l f o t r a n s f e r a s e s i n the b i o s y n t h e s i s o f a r y l s u l f a t e e s t e r s and r e l a t e d compounds formed i n the metabolism o f x e n o b i o t i c s . The b i o s y n t h e s i s o f a r y l s u l f a t e e s t e r s i s accomplished by t r a n s f e r r i n g t h e s u l f a t e group i n PAPS t o a receptor (ROH) t o form ROSO3". Evidence f o r t h e formation o f d i s u l f a t e conjugates o f d i - and t r i - h y d r i c phenols has been reported (26). I n some cases, amines but not t h i o l s can s u b s t i t u t e f o r ROH as acceptors (21). Apparently there i s no c o n c l u s i v e evidence f o r the b i o s y n t h e s i s o f s u l f a t e e s t e r s o f hydroxylamines i n v i v o (which may be due t o the inherent i n s t a b i l i t y o f these compounds); however, the evidence f o r t h e formation and t r a n s i e n t e x i s t e n c e of such compounds i n v i t r o i s c o n v i n c i n g (27-31). Apparently, no one has i s o l a t e d a s u l f o t r a n s f e r a s e i n pure form (21), but i t i s w e l l e s t a b l i s h e d t h a t there are many d i f f e r ent s u l f o t r a n s f erase enzymes 07, 20^, 2JL, 32-39) . Some o f the s u l f o t r a n s f e r a s e s apparently have a high degree o f s u b s t r a t e s p e c i f i c i t y but t h i s c o n c l u s i o n must be v e r i f i e d w i t h p u r i f i e d enzymes• ?


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The i n t r a c e l l u l a r l o c a t i o n o f the s u l f a t e a c t i v a t i n g and s u l f o t r a n s f erase enzymes has not been s t u d i e d f o r many t i s s u e s , but i n t h e l i v e r they are present i n the s o l u b l e f r a c t i o n o f the c e l l . Although s u l f a t e e s t e r formation has been most e x t e n s i v e l y s t u d i e d i n mammalian l i v e r , many t i s s u e s , i n c l u d i n g t h e kidney, i n t e s t i n e , b r a i n , a d r e n a l , mast c e l l s , ovary, and t e s t i s , a l s o have the a b i l i t y t o synthesize PAPS (21) . Powell e_t a l . (40) demonstrated that the gut o f t h e r a t r a p i d l y converted phenol t o phenyl s u l f a t e and have questioned t h e b e l i e f o f others t h a t the l i v e r i s the major organ i n v o l v e d i n t h e metabolism o f compounds o f t h i s nature. T h e i r r e s u l t s support the c o n c l u s i o n t h a t phenols per se are not transported from t h e gut but are conjugated before e n t e r i n g the c i r c u l a t o r y system. The q u a n t i t a t i v e importance o f s u l f a t e e s t e r conjugation v a r i e s w i t h many f a c t o r s which Include the f o l l o w i n g : age o f the animal (35, 4 1 ) ; species o f animal (42) ; t i s s u e ( 4 2 ) ; sex o f a n i mal ( 4 3 ) ; s i z e o f dose (44, 4 5 ) ; s u l f u r n u t r i t i o n a l s t a t e o f a n i mal (46, 4 7 ) ; time a f t e r dosing (47); disease s t a t e (48); s u b s t i t uent e f f e c t s (49); and i n h i b i t o r s (43, 5 0 ) . Roy (20, 2 1 ) , Dodgson (51), Gregory and Robbins (22) , Dodgson and Rose ( 7 ) , and Young and Maw (52) have reviewed the evidence f o r t h e s y n t h e s i s o f s u l f a t e e s t e r s by metabolic routes other than those u t i l i z i n g PAPS. Perhaps the best evidence f o r a l t e r n a t e pathways has been obtained w i t h lower animals such as mollusks, but there are suggestions t h a t other routes may occur i n higher animals as w e l l . A s c o r b i c a c i d 3 - s u l f a t e and unknown s u l f a t e donors have been i m p l i c a t e d . Some proposed mechanisms have been discounted (21); but t h e p o s s i b i l i t y o f a l t e r n a t e routes o f s u l f a t e e s t e r b i o s y n t h e s i s has not been completely i n v e s t i g a t e d . The metabolic f a t e o f some s u l f a t e e s t e r s i n animals has been i n v e s t i g a t e d . S t u d i e s , such as those reported by Flynn e t a l . (53) and Hawkins and Young (54) demonstrated that many s u l f a t e e s t e r s are q u i c k l y e l i m i n a t e d i n the u r i n e w i t h l i t t l e or no metabo l i s m . Park (6) reported t h a t a r y l s u l f a t e s were e l i m i n a t e d i n the u r i n e by a c t i v e t r a n s p o r t . C u r t i s e t a l . (55) compared the r e n a l clearance o f i n u l i n and a s e r i e s o f a r y l s u l f a t e s at d i f f e r ent plasma concentrations and found t h a t s u l f a t e e s t e r s were s e c r e t e d by the r e n a l c e l l s . The c o n t r i b u t i o n o f the r e n a l s e c r e t o r y process t o o v e r a l l u r i n a r y e x c r e t i o n ranged from 22 t o 87%. They concluded that the r a p i d e l i m i n a t i o n of the a r y l e s t e r s s t u d i e d was due t o t h e r a p i d s e c r e t i o n of these compounds r a t h e r than prevention o f t u b u l a r r e s o r p t i o n . However, some s u l f a t e e s t e r s are e x t e n s i v e l y metabolized t o a v a r i e t y of products which i n c l u d e mercapturic a c i d d e r i v a t i v e s (56), doubly conjugated d e r i v a t i v e s (53, 5 7 ) , other compounds formed without removal o f the s u l f a t e group ( 5 8 ) , and other u n i d e n t i f i e d metabolites (59-61). The degree o f metabolism o f s u l f a t e e s t e r s may vary w i t h t h e sex o f the animal (62). Studies have shown that p e r i t o n e a l b a r r i e r s were permeable t o some a r y l s u l f a t e e s t e r s but other b a r r i e r s were n o t ; f o r i n s t a n c e , r a d i o a c t i v i t y


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d i d not pass i n t o the c e n t r a l nervous system when [35s]aryl s u l f a t e e s t e r s were given t o r a t s (63). C u r t i s e t a l . (55) reported t h a t some a r y l s u l f a t e e s t e r s were bound to plasma p r o t e i n s i n v i v o . B i l i a r y s e c r e t i o n , which i s o f q u a n t i t a t i v e importance w i t h some s u l f a t e e s t e r s , can be i n f l u e n c e d by e x t e r n a l f a c t o r s . For i n s t a n c e , Powell et a l . (64) reported t h a t the b i l i a r y e x c r e t i o n of phenolphthalein d i s u l f a t e by the r a t was decreased by admini s t r a t i o n of d i e t h y l s t i l b e s t r o l s u l f a t e and d i e t h y l s t i l b e s t r o l monoglucuronide•


S u l f a t a s e Enzymes Because the p e s t i c i d e chemist f r e q u e n t l y uses s u l f a t a s e enzymes t o cleave s u l f a t e e s t e r conjugates, a b a s i c understanding o f the k i n e t i c c h a r a c t e r i s t i c s and p r o p e r t i e s o f the v a r i o u s members of t h i s d i v e r s e group o f enzymes i s e s s e n t i a l . A t l e a s t s i x gene r a l groups o f enzymes are r e s p o n s i b l e f o r the h y d r o l y s i s o f s u l f a t e e s t e r s which can be c l a s s i f i e d on the b a s i s o f t h e i r subs t r a t e s as: a r y l s u l f a t a s e s , s t e r o i d s u l f a t a s e s , mucopolysaccha r i d e s u l f a t a s e s (chondrosulfatase and heparin s u l f a t a s e s ) , g l y c o s u l f a t a s e s , myrosulfatases, and a l k y l s u l f a t a s e s (22). Roy (65) and Dodgson and Rose (7) have used s i m i l a r c l a s s i f i c a t i o n schemes. This d i s c u s s i o n i s r e s t r i c t e d p r i m a r i l y to the a r y l s u l f a t a s e s because they have been s t u d i e d i n g r e a t e s t d e t a i l and are of most I n t e r e s t to the p e s t i c i d e chemist. The s t u d i e s t h a t l e d t o the d i s c o v e r y of a r y l s u l f a t a s e enzymes have been reviewed ( 7 ) . The general p r o p e r t i e s and c l a s s i f i c a t i o n of these enzymes, as w e l l as k i n e t i c and i n h i b i t o r s t u d i e s , have been summarized (7, 20_ ,22, £5, 66) . Enzymes f o r the h y d r o l y s i s o f a r y l s u l f a t e e s t e r s are widespread i n nature (22, 65), but the most d e t a i l e d s t u d i e s have been conducted w i t h enzymes from mammals, mollusks, and microorganisms (22). The s u b s t r a t e s p e c i f i c i t y and p r o p e r t i e s o f a r y l s u l f a t a s e s from d i f f e r e n t sources vary and f a i l u r e t o recognize t h i s f a c t l e d to confusing and appare n t l y c o n t r a d i c t o r y r e s u l t s i n the e a r l y s t u d i e s ( 7 ) . The more d e t a i l e d s t u d i e s (67-72) which c l a r i f i e d these p o i n t s have been summarized ( 7 ) • I t i s now known t h a t the mammalian l i v e r contains two a r y l s u l f a t a s e s (designated A and B) i n the lysosomes and a t h i r d form (designated C) i n the microsome f r a c t i o n . A r y l s u l f a t a s e A and B from mammalian lysosomes are i n h i b i t e d by S O 4 " , HPO^"", and F~, are not i n h i b i t e d by QT*, have a low pH optimum, and are most a c t i v e i n the h y d r o l y s i s o f substrates such as n i t r o c a t e c h o l s u l f a t e . These mammalian enzymes and a r y l s u l f a t a s e enzymes from other sources t h a t have s i m i l a r s u b s t r a t e s p e c i f i c i t i e s and behavi o r toward i n h i b i t o r s have been c l a s s i f i e d as "Type I I enzymes." I n c o n t r a s t , a r y l s u l f a t a s e C i n the microsome f r a c t i o n of mammali a n l i v e r has a pH optimum of 8 , i s most a c t i v e on simple subs t r a t e s such as £-nitrophenyl s u l f a t e , and i s i n h i b i t e d by CN~ 9

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but not by HPO4 . This mammalian enzyme and a r y l s u l f a t a s e s from other sources w i t h s i m i l a r p r o p e r t i e s have been c l a s s i f i e d as "Type I Enzymes." The v a l i d i t y of the s u b d i v i s i o n of the a r y l s u l f a t a s e s i n t o Type I and Type I I enzymes and i n c o n s i s t e n c i e s that sometimes a r i s e when the m u l t i c r i t e r i a c l a s s i f i c a t i o n system i s used have been discussed (66). This c l a s s i f i c a t i o n system has shortcomings, but i t i s f u n c t i o n a l and should remind the p e s t i c i d e chemist that the p r o p e r t i e s of a r y l s u l f a t a s e s from d i f f e r e n t sources may be q u i t e d i s s i m i l a r . The a r y l s u l f a t a s e s c a t a l y z e the h y d r o l y s i s of the 0-S bond, and t h e only known s u l f a t e acceptor i s water. There i s no e v i dence t h a t a metal i s i n v o l v e d , and the r e a c t i o n i s apparently i r r e v e r s i b l e . N i c h o l l s and Roy (66) suggested t h a t the a c t i v a t i o n energy i s probably about 12-14 Kcal/mole; however, the thermodynamics of the a r y l s u l f a t a s e r e a c t i o n apparently have not been s t u d i e d i n d e t a i l . The s t u d i e s t h a t have been reported on subs t r a t e s and i n h i b i t o r s of the a r y l s u l f a t a s e s , the a c t i v e s i t e s on these enzymes, and the k i n e t i c and p h y s i c a l p r o p e r t i e s of these enzymes have been summarized (7^, 66) . The procedures t h a t have been used t o assay a r y l s u l f a t a s e a c t i v i t y have u s u a l l y i n v o l v e d measuring the l i b e r a t e d phenol c o l o r i m e t r i c a l l y o r determining the a n i o n i c form o f the phenol i n the v i s i b l e o r u l t r a v i o l e t regions o f the spectrum. Dodgson and Spencer (73) reviewed the methods, l i m i t a t i o n s , and problems that have been encountered w i t h these procedures. More recent s t u d i e s have been reported on d i r e c t cytochemical assay of a r y l s u l f a t a s e s (74) , assays f o r s u l f a t a s e s A and B (75, 76) , the i n fluence o f the s t a t e o f molecular aggregation on the enzymic h y d r o l y s i s of a r y l s u l f a t e s (77), the t i s s u e d i s t r i b u t i o n of a r y l s u l f a t ases A and B (76), k i n e t i c c h a r a c t e r i s t i c s and i n h i b i t o r s of a r y l s u l f a t a s e A (78), e l e c t r o p h o r e t i c s e p a r a t i o n and c h a r a c t e r i z a t i o n of a r y l s u l f a t a s e A and B ( 7 9 ) , and evidence that cerebroside s u l f a t e s and a r y l s u l f a t e s are degraded by the same enzyme (80). The l a t t e r r e p o r t i s of i n t e r e s t s i n c e humans w i t h metachromatic leukodystrophy, a human s p h i n g o - l i p i d storage d i s e a s e , are d e f i c i ent i n a r y l s u l f a t a s e A (81). I n d u c t i o n of a l k y l s u l f a t a s e s i n microorganisms has been r e ported (82, 83). Whether i n d u c t i o n a l s o occurs i n higher animals and w i t h other c l a s s e s of compounds, such as a r y l s u l f a t e s , has not been reported but may be worthy of f u r t h e r study. Laboratory

Synthesis

The most w i d e l y used methods f o r the synthesis of a r y l s u l f a t e s employ s u l f u r t r i o x i d e o r S03-amine adducts; the chemistry of s u l f u r t r i o x i d e , and i t s d e r i v a t i v e s has been reviewed i n d e t a i l (84). Many reagents have been used i n t h i s type o f s u l f a t i o n react i o n i n c l u d i n g c h l o r o s u l f o n i c a c i d (45, 77, 85-89), t r i e t h y l a m i n e s u l f u r t r i o x i d e (90, 9 1 ) , and p y r i d i n e s u l f u r t r i o x i d e (92, 93)• Other reagents t h a t have been used i n the s y n t h e s i s of s u l f a t e



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e s t e r s i n c l u d e p y r o s u l f a t e (94). fuming s u l f u r i c a c i d , and s u l f a m i c a c i d (84) . The use o f c h l o r - t ^ S ] s u l f o n i c a c i d i n the p r e p a r a t i o n of [ S ] - l a b e l e d a r y l s u l f a t e e s t e r s has been d e s c r i b e d (S3, 54, 95). Although not widely used by p e s t i c i d e chemists, the r e a c t i o n of H2SO4 w i t h a v a r i e t y of compounds i n the presence of d i c y c l o hexylcarbodiimide and a p o l a r s o l v e n t (96-98) warrants c a r e f u l c o n s i d e r a t i o n . This method gives s u l f a t e e s t e r s i n good y i e l d and i s e s p e c i a l l y u s e f u l i n the p r e p a r a t i o n of s u l f a t e e s t e r s o f compounds t h a t are unstable to reagents such as c h l o r o s u l f o n i c a c i d and p y r i d i n e s u l f u r t r i o x i d e . Moreover, i f the c o n d i t i o n s are j u d i c i o u s l y a d j u s t e d , t h i s procedure can be used f o r the s e l e c t i v e s u l f a t i o n of p o l y f u n c t i o n a l molecules (98). This method i s p a r t i c u l a r l y good f o r the s y n t h e s i s of T ^ S ] - s u l f a t e e s t e r s because [35so^] i s r e a d i l y a v a i l a b l e , r e l a t i v e l y inexpensive, and i s used d i r e c t l y without conversion to c h l o r o s u l f o n i c a c i d or p y r i d i n e sulfur trioxide. Mumma (99) reported t h a t a s c o r b i c a c i d 2 - s u l f a t e and isopropopylidene a s c o r b i c a c i d s u l f a t e acted as an i n v i t r o s u l f a t i n g agent at e l e v a t e d temperatures and/or i n the presence of o x i d i z i n g agents. For example, a l c o h o l s such as 1-octanol and 33c h o l e s t a n o l were r e a d i l y s u l f a t e d when incubated w i t h i s o p r o p y l i dene a s c o r b i c a c i d s u l f a t e i n the presence of bromine or when incubated at 100°C. Quadri et a l . (100) and Mumma et a l . (101) reported on the s y n t h e s i s and c h a r a c t e r i z a t i o n of L - a s c o r b i c a c i d 2 - s u l f a t e . The p o s s i b l e use of a s c o r b i c a c i d s u l f a t e and/or i t s d e r i v a t i v e s as a p r e p a r a t i v e method f o r s u l f a t i n g phenols appare n t l y has not been reported but may be worthy o f f u r t h e r evaluation. Recently, Nagasawa and Yoshidome (89) reported on the C u ( I I ) c a t a l y z e d r e a c t i o n of 8 - q u i n o l y l s u l f a t e i n the s y n t h e s i s o f D-galactose 6 - s u l f a t e , adenosine 5 ' - s u l f a t e and dextran s u l f a t e . Whether t h i s procedure can be used to prepare s u l f a t e e s t e r s o f phenols, a l c o h o l s , and s t e r o i d s w a i t s f u r t h e r i n v e s t i g a t i o n . Boyland and Nery (102) reported on the s u l f a t i o n of phenylhydroxy lamine and r e l a t e d compounds w i t h p y r i d i n e s u l f u r t r i o x i d e and other reagents t o form N - s u l f o n i c and O - s u l f o n i c a c i d d e r i v a t i v e s (the product formed depended on the r e a c t i o n c o n d i t i o n s and b l o c k i n g groups used). These compounds were i s o l a t e d as t h e i r ammonium and potassium s a l t s . Boyland and Nery (102) a l s o made the important observation t h a t phenyl hydroxylamine-O-sulfonic a c i d rearranged t o 2-amino-phenyl s u l f a t e . The b i o s y n t h e s i s of s u l f a t e e s t e r s w i t h i n v i t r o t i s s u e prepa r a t i o n s , f o r t i f i e d w i t h PAPS or PAPS generating systems, has been used by many workers (9», 12, 13, 32, 36, 37^, 103-109). This technique lends i t s e l f w e l l t o the s y n t h e s i s o f [ ^ S ] - l a b e l e d s u l fate esters. The p h e n o l s u l f o t r a n s f e r a s e r e a c t i o n i s r e a d i l y r e v e r s i b l e when the a r y l s u l f a t e e s t e r i n v o l v e d i s r e a c t i v e (34, 110, 111). For i n s t a n c e , Brunngraber (110) demonstrated the t r a n s f e r o f


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s u l f a t e from £-nitrophenyl s u l f a t e t o m-aminophenol i n the presence of phenol s u l f o t r a n s f e r a s e and PAP. This f a c t has been e x p l o i t e d as a convenient assay procedure. However, the p o s s i b l e use o f t h i s technique f o r t h e s y n t h e s i s o f s u l f a t e e s t e r s should be cons i d e r e d . This approach could be e s p e c i a l l y u s e f u l when the acceptor molecule has one o r more l a b i l e l i n k a g e s .


Properties A r y l s u l f a t e e s t e r s are u s u a l l y s t a b l e as t h e i r a l k a l i s a l t s , e s p e c i a l l y when s t o r e d i n t h e dark at low temperatures. Havinga et a l . (112) described t h e photochemical a c c e l e r a t e d h y d r o l y s i s of n i t r o p h e n y l s u l f a t e s . A r y l s u l f a t e e s t e r s are h i g h l y s o l u b l e i n water and appreciably s o l u b l e i n a l c o h o l s . An e s p e c i a l l y usef u l s o l v e n t i s N-butanol because i t can often be used t o e x t r a c t a r y l s u l f a t e e s t e r s from aqueous s o l u t i o n . The f a c t that s u l f a t e e s t e r s form s a l t s w i t h organic bases such as j j - t o l u i d e n e (113) , £-bromoaniline (114), methylene blue (115, 116), and the amlnoa c r i d i n e s (72) i s u s e f u l f o r t h e i s o l a t i o n of a r y l s u l f a t e s because most o f them can be e x t r a c t e d from aqueous s o l u t i o n s w i t h organic s o l v e n t s . Dodgson e t a l . (72) used 5-aminoacridine t o i s o l a t e the a r y l s u l f a t e s excreted i n t h e u r i n e o f r a b b i t s fed £-chlorophenol and r e l a t e d compounds. Roy and Trudinger (117) and Young and Maw (52) discussed t h e a p p l i c a t i o n o f t h i s p r i n c i p l e t o the i s o l a t i o n and i d e n t i f i c a t i o n of a r y l s u l f a t e s . The e a r l y work o f Burkhardt (118, 119) and others e s t a b l i s h e d that a r y l s u l f a t e e s t e r s are r e a d i l y hydrolyzed by a c i d s ; the r a t e of a c i d h y d r o l y s i s i s increased when t h e s u l f a t e moiety i s a t t a c h ed t o a p o s i t i o n o f low e l e c t r o n a v a i l a b i l i t y . For example, £n i t r o p h e n y l s u l f a t e i s e a s i l y hydrolyzed w i t h a c i d . The mechanism of a c i d h y d r o l y s i s o f a r y l s u l f a t e s has been s t u d i e d (120-122). Roy and Trudinger (117) discussed the problems w i t h a r t i f a c t f o r mation when some s u l f a t e e s t e r s are a c i d hydrolyzed. Batts (123) reported t h a t t h e r a t e o f h y d r o l y s i s o f s u l f a t e e s t e r s was i n creased by a f a c t o r of 10^ when the s o l v e n t was changed from pure water t o moist dioxane. L a t e r , Goren and Kochansky (124) extended these s t u d i e s and found t h a t t h e s o l v o l y s i s r e q u i r e d i n i t i a t i o n by t r a c e s o f i m p u r i t i e s , presumably a c t i n g as an e l e c t r o p h i l e . For i n s t a n c e , 2-octanol s u l f a t e i n clean t e f l o n v e s s e l s was s t a b l e t o hot, moist dioxane. In c o n t r a s t t o t h e i r l a b i l i t y under a c i d c o n d i t i o n s , most a r y l s u l f a t e s a r e q u i t e s t a b l e under b a s i c c o n d i t i o n s 07 , S7_ 117119). For example, Burkhardt and Lapworth (87) heated a r y l s u l f a t e s t o 150°C f o r 4 hours i n strong a l k a l i o r h a l f - c o n c e n t r a t e d ammonia t o b r i n g about h y d r o l y s i s . 9

Separation

and P u r i f i c a t i o n Techniques

A s s a n d r i and P e r a z z i (125) reported on t h e s e p a r a t i o n o f phenolic O-glucuronides and p h e n o l i c s u l f a t e e s t e r s by m u l t i p l e


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l i q u i d - l i q u i d p a r t i t i o n . T h e i r methods i n v o l v e d a counter current technique w i t h continuous flow of the s o l v e n t s . However, the I s o l a t i o n o f s u l f a t e e s t e r s from b i o l o g i c a l f l u i d s , such as u r i n e , by t h i s technique r e q u i r e d p r e - p u r i f i c a t i o n o f the crude m a t e r i a l before the counter current f r a c t i o n a t i o n procedure; i m p u r i t i e s , such as s a l t s , i n t e r f e r e d w i t h the p a r t i t i o n systems. Because of the p o l a r nature o f a r y l s u l f a t e e s t e r s , i t i s not s u r p r i s i n g t h a t i o n exchange chromatography has been used extens i v e l y i n the p u r i f i c a t i o n o f these compounds (12, 13, 45, 88, 126-131. Sephadex G-10 columns e l u t e d w i t h water (45, 88, 103, 130, 131), Sephadex G-15 columns e l u t e d w i t h water (132), and Sephadex LH-20 columns e l u t e d w i t h e i t h e r CH3OH or H 0 (45, 103, 129-131) have been used f o r the p u r i f i c a t i o n o f a r y l s u l f a t e s . I t should be noted t h a t mixed s a l t forms o f s u l f a t e e s t e r s are e x c r e t ed by animals and t h a t these d i f f e r e n t s a l t forms may be separated on Sephadex LH-20 columns e l u t e d w i t h CH3OH (103). Other chromatographic procedures t h a t have been used t o separate and p u r i f y s u l f a t e e s t e r conjugates o f p e s t i c i d a l compounds i n c l u d e : B i o g e l P-2 columns (131) ; XAD-2 columns (94^, 116) ; Porapak Q columns (88, 129); and paper chromatography (88, 133, 134). FaakonmaTci (135) reported on a d i r e c t gas chromatographic a n a l y s i s o f s t e r o i d s u l f a t e s and glucuronides. Mass spectroscopy showed t h a t the s t e r o i d s u l f a t e s l o s t H2SO4 and a double bond was formed g i v i n g a m o l e c u l a r i o n 18 mass u n i t s lower than t h a t o f the f r e e s t e r o l . I n c o n t r a s t , the g l u c u r o n i c a c i d conjugates gave the parent s t e r o l . The a p p l i c a b i l i t y o f t h i s procedure, i f any, t o a r y l s u l f a t e s and glucuronides apparently has not been reported. P r e l i m i n a r y s t u d i e s w i t h e l e c t r o n impact mass spectrometry a t t h i s l a b o r a t o r y i n d i c a t e d that a r y l s u l f a t e e s t e r s (K s a l t s ) thermally degrade t o give a fragment corresponding to the phenol ( u s u a l l y base peak) and fragments a t lower masses.


2

D e r i v a t i z a t i o n Procedures There apparently i s l i t t l e or no i n f o r m a t i o n i n the l i t e r ature concerning attempts t o d e r i v a t i z e the s u l f a t e group i n a r y l s u l f a t e s . McKenna and Norymberskl (136), P a s q u a l i n i et a l . (137) , and E m i l i o z z i (138) reported on the formation of methylated der i v a t i v e s when s t e r o i d s u l f a t e s were t r e a t e d w i t h diazomethane• Studies at t h i s l a b o r a t o r y i n d i c a t e d t h a t a r y l s u l f a t e s were not methylated by diazomethane o r , i f they were, the products were not s t a b l e ; the l a t t e r e x p l a n a t i o n seems most l i k e l y . However, f u r t h e r study i s needed t o c l a r i f y t h i s p o i n t . In some cases, i t i s p o s s i b l e t o d e r i v a t i z e other f u n c t i o n a l groups i n a molecule without c l e a v i n g or d e r i v a t i z i n g the s u l f a t e group. For i n s t a n c e , Dodgson e t a l . (70) methylated the f r e e h y d r o x y l o f a monosulfate e s t e r of 4-chlorocatechol i s o l a t e d from r a b b i t u r i n e . The m e t h y l a t i o n of the monosulfate e s t e r s o f i s o p r o p y l 3,4-dihydroxycarbanilate w i t h diazomethane ( l e a v i n g the s u l f a t e e s t e r group i n t a c t ) f o l l o w e d by replacement o f the s u l f a t e


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e s t e r w i t h an acetoxy group made p o s s i b l e the c h a r a c t e r i z a t i o n and subsequent s y n t h e s i s and i d e n t i f i c a t i o n o f propham metabolites (140). A one-step method f o r r e p l a c i n g t h e s u l f a t e group i n a r y l and s t e r o i d s u l f a t e e s t e r s w i t h an acetoxy group (139) i s u s e f u l f o r c h a r a c t e r i z a t i o n o f compounds that are unstable t o conventional h y d r o l y s i s c o n d i t i o n s . For example, u t i l i z a t i o n o f t h i s technique made i t p o s s i b l e t o i d e n t i f y c a r b a r y l metabolites i n chicken u r i n e as conjugated forms o f 1,5-dehydroxynaphthalene and 1 , 5 , 6 - t r i hydroxynaphthalene, compounds that are unstable t o normal h y d r o l y s i s c o n d i t i o n s (103). This technique was a l s o used i n the chara c t e r i z a t i o n o f s u l f a t e e s t e r - c o n t a i n i n g metabolites of propham (129, 140) and £-chlorophenyl N-methylcarbamate (45, 131) . Spectral Analysis Hearse e t a l . (95) reported t h a t a s e r i e s o f a r y l s u l f a t e e s t e r s e x h i b i t e d s t r o n g absorption from 240-280 my (maxima 250-275 my); whereas t h e parent phenols absorbed s t r o n g l y from 270-310 my (maxima 280-295 my). Moreover, the e x t i n c t i o n c o e f f i c i e n t of the phenols was much g r e a t e r than t h a t of the s u l f a t e e s t e r s . The marked s h i f t i n t h e Amax and t h e i n c r e a s e i n the e x t i n c t i o n coe f f i c i e n t ' a s s o c i a t e d w i t h t h e conversion of the p h e n o l i c hydroxy1 to i t s i o n i z e d form were not shown by t h e corresponding a r y l s u l f a t e e s t e r . This behavior has been e x p l o i t e d t o develop assays f o r t h e h y d r o l y s i s o f a r y l s u l f a t e s (73, 141). Nuclear magnetic resonance s t u d i e s (NMR) a t t h i s l a b o r a t o r y have demonstrated t h a t a r y l s u l f a t e e s t e r s s h i f t the absorption of r i n g protons downfield r e l a t i v e t o t h e i r p o s i t i o n i n the spectrum o f t h e parent phenol. As expected, the s h i f t was g r e a t e s t f o r t h e proton ortho t o t h e s u l f a t e group. For i n s t a n c e , absorpt i o n s o f t h e protons ortho and meta t o t h e hydroxy i n £-nitrophenol were a t 6.93 and 8.10 ppm, r e s p e c t i v e l y , (solvent-d£-DMSO) and these absorptions were s h i f t e d t o 7.4 and 8.18 ppm, respect i v e l y , i n t h e spectrum o f £-nitrophenyl s u l f a t e . NMR s p e c t r o s copy has been used i n a s s i g n i n g s t r u c t u r e s t o the mono and d i s u l f a t e e s t e r s o f 4-chlorocatechol (131). Further s t u d i e s are underway t o more thoroughly i n v e s t i g a t e t h e e f f e c t of s u l f a t e e s t e r s on NMR absorption o f aromatic compounds. Since a l k a l i s a l t s of s u l f a t e e s t e r s are s o l i d s and are only s l i g h t l y s o l u b l e i n most organic s o l v e n t s , the i n f r a r e d s p e c t r a of these compounds are u s u a l l y measured i n a KBr p e l l e t o r i n a N u j o l m u l l . Chihara (142) reported t h a t the s p e c t r a of s u l f a t e e s t e r s obtained from KBr p e l l e t s and mulls were not appreciably d i f f e r e n t . However, i t should be noted that the i n f r a r e d s p e c t r a of d i f f e r e n t s a l t forms o f a r y l s u l f a t e e s t e r s are d i s t i n c t l y d i f f e r e n t (103). Chihara (142) s y s t e m a t i c a l l y s t u d i e d t h e i n f r a red s p e c t r a o f a s e r i e s o f a l k y l and a r y l s u l f a t e e s t e r s . He assigned t h e two bands at 1210-1220 and 1240-1260 cm" t o the S 0 asymmetric s t r e t c h i n g v i b r a t i o n ; these absorptions were very 1

3


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s t r o n g and not g r e a t l y s h i f t e d by a v a r i e t y o f s u b s t i t u e n t s . He assigned t h e s t r o n g a b s o r p t i o n a t 1040-1081 cm" t o the SO3 symm e t r i c v i b r a t i o n and the l e s s i n t e n s e bands a t 550-590 cm-i (sometimes s p l i t ) and 617-650 c n r t o SO3 bending v i b r a t i o n s . The abs o r p t i o n from 757 t o 838 c n r was assigned t o the S-O-C s t r e t c h . L l o y d e t a l . (143) s t u d i e d the i n f r a r e d s p e c t r a of the s u l f a t e e s t e r s o f a l c o h o l s , amino a l c o h o l s , and hydroxylated amino a c i d s and reported s i m i l a r conclusions ( a b s o r p t i o n bands a t 1210-1260 cm" , 1030-1050 cm" , and 770-810 cm" , assigned t o the s u l f a t e e s t e r ) . Related s t u d i e s on t h e i n f r a r e d s p e c t r a o f p o l y s a c c h a r i d e s u l f a t e s (144) and monosaccharide s u l f a t e s (145) have been r e p o r t ed. Hummel (146) discussed the i n f r a r e d s p e c t r a of primary (abs o r p t i o n bands a t 1220-1267 cm" , 1075-1100 cm" , and 834-840 cm" ) and secondary ( a b s o r p t i o n bands 1228-1250 cm" , 1063-1075 cm" , and 926-945 cm"*-) s u l f a t e e s t e r s i n s u r f a c t a n t compounds. Colthup eit a l . (147) presented the spectrum o f n-dodecyl s u l f a t e which showed a b s o r p t i o n bands a t approximately 820-840 cm" , 1 2 0 0 1280 cm" , and 1060-1080 cm" which were assigned t o the s u l f a t e moiety. I n f r a r e d spectroscopy has been used t o c h a r a c t e r i z e s u l f a t e e s t e r s o f drugs (94, 148), s t e r o i d s (96, 138), and s u l f a t e e s t e r c o n t a i n i n g metabolites o f p e s t i c i d e s which i n c l u d e mobam (88) , £-chlorophenylmethylcarbamate (45, 131), propham (129, 140), c a r b a r y l (103), chlorpropham (134), and barban (134). The technique o f l a s e r i o n i z a t i o n mass spectrometry (149) has been used by Mumma and V a s t o l a (150) t o o b t a i n the mass s p e c t r a of t h e sodium and potassium s a l t s o f 1 - h e x y l , 1 - d e c y l , and 1-octadecyl s u l f a t e . The molecular species p l u s a c a t i o n ([M + N a ] o r [M + K ] ) was one o f the more i n t e n s e peaks i n the s p e c t r a but no other "organic i o n s " were observed. "Inorganic i o n s " that were abundant i n the s p e c t r a i n c l u d e d [NaS04]+, [ ^ 3 8 0 4 ] * , and t h e corresponding potassium-containing fragments. Approximatel y 1 mg o f sample was used f o r these assays; but the authors r e ported "good s p e c t r a can be obtained on l e s s sample." This procedure has been used t o c h a r a c t e r i z e a number o f s t e r o i d , a l k y l , and a r y l s u l f a t e e s t e r s (97, 9 8 ) . R e c e n t l y , Games e t a l . (151) p u b l i s h e d a b r i e f report d e a l i n g w i t h t h e u t i l i t y o f f i e l d d e s o r p t i o n mass spectrometry i n the a n a l y s i s o f s u l f a t e e s t e r s and r e l a t e d compounds. They found t h a t n-hexyl, n - d e c y l , and n-undecyl s u l f a t e s gave quasi molecular ions at m/e 259, 315, and 329, r e s p e c t i v e l y , but no fragment ions were observed. C y c l o h e x y l p h e n y l - 4 - s u l f a t e gave a quasi-molecular i o n ([M + K ] ) at m/e 333 but a l s o gave an i o n a t m/e 176, presumably r e s u l t i n g from cleavage and hydrogen t r a n s f e r t o form the parent phenol. Thus, there i s reason f o r optimism t h a t f i e l d - d e s o r p t i o n mass spectrometry may be a u s e f u l t o o l . However, much a d d i t i o n a l work needs t o be done t o determine i f t h i s approach w i l l be o f p r a c t i c a l importance i n t h e i d e n t i f i c a t i o n o f s u l f a t e e s t e r s — p a r t i c u l a r l y s u l f a t e e s t e r s from b i o l o g i c a l preparations where c o m p l i c a t i n g f a c t o r s , such as mixed s a l t forms, may be a problem. H o p e f u l l y , i n f o r m a t i o n t o answer t h i s and other questions about 1

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f i e l d - d e s o r p t i o n mass spectrometry of s u l f a t e e s t e r s w i l l soon be available.


General D i s c u s s i o n There i s a l a r g e and growing body of i n f o r m a t i o n concerning the b i o s y n t h e s i s , chemical s y n t h e s i s , i s o l a t i o n , c h a r a c t e r i z a t i o n , and enzymology of the s u l f a t e e s t e r s . However, a review of the published l i t e r a t u r e d e a l i n g w i t h p e s t i c i d e metabolism reveals that many p e s t i c i d e chemists are not f u l l y u s i n g the i n f o r m a t i o n and technology t h a t i s a v a i l a b l e . For i n s t a n c e , i n most of the r e ported s t u d i e s , the s u l f a t e e s t e r s were hydrolyzed e i t h e r chemica l l y or e n z y m a t i c a l l y and then only the "nonpolar" h y d r o l y s i s product was i d e n t i f i e d . Because some of these compounds, such as the N-hydroxy s u l f a t e s , are potent b i o l o g i c a l agents (27-31, 152-154), the i s o l a t i o n and i d e n t i f i c a t i o n of the i n t a c t molecule i s import a n t . The observation by Boyland and Nery (102) that the s u l f a t e e s t e r of phenyl hydroxylamine rearranged to 2-amino phenyl s u l f a t e suggests t h a t a r t i f a c t s may be produced by c o n d i t i o n s such as those used t o hydrolyze conjugated m e t a b o l i t e s . In many i n s t a n c e s , s t r u c t u r e s of s u l f a t e e s t e r s have been assigned on the b a s i s of enzyme h y d r o l y s i s s t u d i e s and c h a r a c t e r i z a t i o n of only the h y d r o l y s i s product. I n c o r r e c t assignment of s t r u c t u r e because of enzyme preparations that are contaminated w i t h other h y d r o l y t i c enzymes, as w e l l as contaminates from nonezymatic h y d r o l y s i s , are always p o s s i b i l i t i e s that must be considered. Often the markedly d i f f e r e n t p r o p e r t i e s of Type I and Type I I s u l fatases (see previous d i s c u s s i o n ) have been ignored i n s e l e c t i n g assay c o n d i t i o n s and/or i n s e l e c t i n g the type of enzyme to be used f o r the h y d r o l y s i s of d i f f e r e n t c l a s s e s of compounds. Some workers have synthesized the suspected s u l f a t e e s t e r and then c h a r a c t e r i z e d t h e i r unknown metabolites by co-chromatography s t u d i e s only. This i s unfortunate because a d d i t i o n a l and u s u a l l y d e f i n i t i v e d a t a can be obtained by comparative UV, NMR, and IR spectroscopy. These i n s t r u m e n t a l procedures are not d e s t r u c t i v e and r e q u i r e only s m a l l samples ( f o r UV and IR, a sample of 10 ug or l e s s i s u s u a l l y s u f f i c i e n t ) . We have found IR spectroscopy to be e s p e c i a l l y u s e f u l i n c h a r a c t e r i z i n g s u l f a t e e s t e r conjugated p e s t i c i d e m e t a b o l i t e s ; a l l of the s u l f a t e e s t e r s that we have examined have shown the c h a r a c t e r i s t i c absorptions p r e v i o u s l y discussed and the f i n g e r p r i n t region almost i n v a r i a b l y showed sharp, intense bands that are i d e a l f o r comparative IR spectroscopy s t u d i e s . Most p e s t i c i d e chemists have not confirmed the s t r u c t u r e of suspected s u l f a t e e s t e r conjugated metabolites by s y n t h e s i s . This i s s u r p r i s i n g i n l i g h t of the f a c t t h a t there are s e v e r a l methods i n the l i t e r a t u r e f o r the synthesis of s u l f a t e e s t e r s i n c l u d i n g methods that are s u i t a b l e f o r the s u l f a t i o n of compounds w i t h r e l atively l a b i l e linkages. Information concerning the b i o l o g i c a l a c t i v i t y of s u l f a t e e s t e r conjugates of p e s t i c i d e s and/or t h e i r primary metabolites i s


6.

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97

very l i m i t e d . Studied t o determine the e f f e c t o f d i e t a r y f a c t o r s , drugs, hormones, disease s t a t e s , and r e l a t e d f a c t o r s on the s u l f a t e e s t e r conjugation o f p e s t i c i d e s and t h e i r primary m e t a b o l i t e s by animals would be o f v a l u e . The f a t e o f s u l f a t e e s t e r s i n s o i l and p l a n t systems would a l s o be o f i n t e r e s t . F i n a l l y , there i s a need f o r b e t t e r and f a s t e r methods o f i s o l a t i n g s u l f a t e e s t e r s from b i o l o g i c a l p r e p a r a t i o n s . The e x i s t ing techniques f o r c h a r a c t e r i z a t i o n o f s u l f a t e e s t e r s need t o be improved. A d d i t i o n a l s t u d i e s on NMR and f i e l d d e s o r p t i o n mass spectrometry o f t h i s c l a s s o f compounds may be e s p e c i a l l y f r u i t f u l .


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Bound and Conjugated Pesticide Residues

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