Photomodification and Singlet Oxygen Generation in Membranes

Chapter 3

Photomodification and Singlet Oxygen Generation in Membranes Dennis Paul Valenzeno

Downloaded by TUFTS UNIV on June 3, 2018 | https://pubs.acs.org Publication Date: May 7, 1987 | doi: 10.1021/bk-1987-0339.ch003

Department of Physiology and K. U. Kidney and Urology Research Center, University of Kansas Medical Center, Kansas City, KS 66103

Photomodification of cell membranes, which in many cases is critical for cell k i l l i n g , is governed by the properties of membrane associated sensitizer. The heterogeneous structure of biological membranes can be an important factor in photosensitization reactions. Sensitizers and protective agents may associate preferentially with the hydrophobic membrane core, may accumulate at the aqueous interface or may bind to membrane proteins. Such localization effects can alter photomodification rates. Although singlet oxygen can diffuse across membrane interfaces in high yield in some cases, membrane associated sensitizer mediates most membrane photomodifications. The membrane environment can influence singlet oxygen generation. Model studies have shown that singlet oxygen quantum yields increase with decreasing solvent polarity. In liposomes or micelles both quantum yields and lifetimes are increased. Aggregation states of sensitizers are changed in the membrane environment leading to alteration of singlet oxygen production. Finally increases in temperature can increase singlet oxygen production due to effects on membrane fluidity.

The goal o f t h i s chapter i s t o d e s c r i b e the c h a r a c t e r i s t i c features of s i n g l e t oxygen g e n e r a t i o n i n membranes as they a r e c u r r e n t l y understood. Membrane p h o t o m o d i f i c a t i o n has been s i n g l e d o u t f o r s p e c i a l c o n s i d e r a t i o n f o r two major reasons. F i r s t recent years have seen an e x p l o s i o n o f i n t e r e s t i n membrane phenomena as the s c i e n t i f i c community has become aware that c e l l u l a r membranes a r e much more than mere gossamer bags t h a t h o l d the i n s i d e i n and the o u t s i d e o u t . Second i n t h e i n s t a n c e s where c e l l u l a r , t i s s u e and organism p h o t o m o d i f i c a t i o n has been examined i n d e t a i l c e l l membranes have r e p e a t e d l y been i d e n t i f i e d as c r i t i c a l t a r g e t s o f m o d i f i c a t i o n ( 1 - 7 ) .

0097-6156/87/0339-0039$06.00/0 © 1987 American Chemical Society

Heitz and Downum; Light-Activated Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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The

LIGHT-ACTIVATED PESTICIDES

Membrane Environment:

B i o l o g i c a l membranes. Not o n l y a r e membranes c r i t i c a l cellular components and c r i t i c a l t a r g e t s f o r p h o t o m o d i f i c a t i o n , they a l s o present a unique environment f o r p h o t o s e n s i t i z e r s which generate s i n g l e t oxygen. I n f a c t i f t h i s were not the case we would not need to c o n s i d e r membrane s e n s i t i z a t i o n as a separate topic. The c h a r a c t e r i s t i c s of s i n g l e t oxygen g e n e r a t i o n by s e n s i t i z e r s i n aqueous s o l u t i o n would a p p l y . As we s h a l l see t h i s i s not the case. Membranes present an environment that d i f f e r s from the s u r r o u n d i n g medium not o n l y i n p o l a r i t y , water content and d i e l e c t r i c c o n s t a n t , but they a r e heterogenous s t r u c t u r e s which present a v a r i e t y of domains w i t h which s e n s i t i z e r s can a s s o c i a t e and from which they can act. Current concepts of the s t r u c t u r e of c e l l membranes a r e based on the f l u i d mosaic model of S i n g e r and N i c o l s o n ( 8 ) . In this view, F i g u r e 1A, the membrane p h o s p h o l i p i d s a r e arranged i n a f l u i d b i l a y e r . T h e i r h y d r o p h o b i c , hydrocarbon t a i l s a r e o r i e n t e d toward the center of the b i l a y e r e x p o s i n g t h e i r p o l a r head groups t o the aqueous environment a t e i t h e r s u r f a c e . T h i s arrangement is s t a b i l i z e d by the h y d r o p h o b i c f o r c e s between the p h o s p h o l i p i d s and does not i n v o l v e c o v a l e n t bonding. The m a j o r i t y of the p h o s p h o l i p i d s are thus f r e e to d i f f u s e w i t h i n the plane of the membrane, but move with difficulty from one s u r f a c e of the b i l a y e r to the o t h e r . Membrane p r o t e i n s a r e i n s e r t e d i n t o the l i p i d b i l a y e r , e i t h e r p a r t way or e n t i r e l y spanning the b i l a y e r (so c a l l e d i n t e g r a l or i n t r i n s i c proteins). The p o r t i o n s of these p r o t e i n s which a r e i n c o n t a c t w i t h the h y d r o p h o b i c i n t e r i o r of the b i l a y e r a r e composed of a h i g h p r o p o r t i o n of hydrophobic amino a c i d s , w h i l e the p o r t i o n s exposed at the aqueous i n t e r f a c e have a h i g h p r o p o r t i o n of h y d r o p h i l i c amino acids. Thus the p r o t e i n s a r e a l s o s t a b i l i z e d i n p o s i t i o n by h y d r o p h o b i c f o r c e s and have the same a b i l i t y to d i f f u s e i n the p l a n e of the b i l a y e r but not a c r o s s it. Both the p r o t e i n s and p h o s p h o l i p i d s can have c a r b o h y d r a t e groups a t t a c h e d t o them, b u t such groups have been found o n l y at the o u t s i d e s u r f a c e of the c e l l . Most animal c e l l membranes have a v a r i a b l e content of c h o l e s t e r o l i n t e r s p e r s e d w i t h the p h o s p h o l i p i d s . The p r o p o r t i o n of c h o l e s t e r o l i s e s p e c i a l l y h i g h i n the membrane of the r e d b l o o d c e l l , which i s the membrane s t u d i e d most e x t e n s i v e l y . The most s i g n i f i c a n t m o d i f i c a t i o n of these ideas that has occurred i n recent y e a r s has been the d i s c o v e r y that i n many instances i n t e g r a l membrane p r o t e i n s a r e r e s t r i c t e d i n t h e i r m o t i o n by an i n t r a c e l l u l a r s k e l e t o n of p e r i p h e r a l ( o r e x t r i n s i c ) membrane p r o t e i n s that serve to anchor some of the i n t r i n s i c proteins i n l o o s e l y f i x e d p o s i t i o n s . I n the red c e l l the c y t o s k e l e t a l network of p e r i p h e r a l membrane p r o t e i n s l i e s j u s t below the membrane surface and anchors i n t e g r a l p r o t e i n s , which span the b i l a y e r , at p e r i o d i c p o i n t s v i a a p r o t e i n component known as a n k y r i n ( 9 , 1 0 ) . The r e s u l t of the membrane s t r u c t u r e j u s t d e s c r i b e d i s t h a t the i n t e r i o r of the membrane has the c h a r a c t e r i s t i c s of the i n t e r i o r of a lipid bilayer. The d i e l e c t r i c constant ( p o l a r i t y ) i s very low (2-3) in this region. L i p o p h i l i c s o l u t e s can be expected t o p a r t i t i o n readily i n t o t h i s domain. Water i s present i n g r e a t l y reduced c o n c e n t r a t i o n w i t h some i n v e s t i g a t o r s c l a i m i n g t h a t the b i l a y e r i s



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d e v o i d of w a t e r . Water p e r m e a b i l i t y of most membranes i s , however, quite high. The o t h e r s i g n i f i c a n t f e a t u r e of the membrane environment which deserves comment i s the i n t e r f a c i a l r e g i o n . This i s a region e x t e n d i n g r o u g h l y from the g l y c e r o l backbone of the p h o s p h o l i p i d s away from the membrane to the end of the a t t a c h e d c a r b o h y d r a t e m o i e t i e s . T h i s r e g i o n i s of i n t e r m e d i a t e p o l a r i t y between the b i l a y e r i n t e r i o r and the aqueous environment ( d i e l e c t r i c c o n s t a n t of about 10). Due to the p o l a r n a t u r e of the charged groups at the membrane i n t e r f a c e , the s u r f a c e of most b i o l o g i c a l membranes has a net n e g a t i v e charge. T h i s s u r f a c e charge can modify the d i s t r i b u t i o n of charged s o l u t e s near i t . I n p a r t i c u l a r the c o n c e n t r a t i o n of c a t i o n s i s h i g h e r and the c o n c e n t r a t i o n of a n i o n s i s lower w i t h i n a few angstroms of the s u r f a c e than i n the b u l k s o l u t i o n a d j a c e n t to the membrane. I n t r a n s p o r t s t u d i e s i t has even been p o s s i b l e to d i s c e r n the e f f e c t s of l o c a l s u r f a c e charge, i . e . charged groups l o c a t e d near the opening of a p r o t e i n a c e o u s channel through the membrane ( 1 1 ) . Water p r e s e n t near the i n t e r f a c e i s thought to be a l i g n e d by the charged groups i n t o a s t r u c t u r e more l i k e i c e than l i q u i d w a t e r . Membrane model systems. Model systems have been v e r y v a l u a b l e as guides to u n d e r s t a n d i n g the c h a r a c t e r i s t i c s of s i n g l e t oxygen i n membrane systems. However, the r e s u l t s must a l s o be v e r i f i e d i n b i o l o g i c a l membranes s i n c e the assembly of p h o s p h o l i p i d s and p r o t e i n s of a c e l l membrane i s s i g n i f i c a n t l y more complex than most model systems. Still, in many i n s t a n c e s models p r o v i d e the o n l y information currently available. The model systems most o f t e n employed are m i c e l l e s or l i p o s o m e s , ( F i g u r e I B ) . The former are aqueous d i s p e r s i o n s of amphipathic molecules. These m o l e c u l e s which have a h y d r o p h o b i c and h y d r o p h i l i c p o r t i o n spontaneously form aggregates i n aqueous s o l u t i o n such that the i n t e r i o r of the a g g r e g a t e , or m i c e l l e , c o n t a i n s the h y d r o p h o b i c p o r t i o n s and thus mimics the membrane i n t e r i o r . The a r e a of c o n t a c t w i t h water mimics the membrane i n t e r f a c i a l r e g i o n and can be charged of e i t h e r s i g n , or uncharged depending on the s t r u c t u r e of the a m p h i p a t h i c m o l e c u l e used. Liposomes are membranous s t r u c t u r e s which resemble soap b u b b l e s . Many a m p h i p a t h i c m o l e c u l e s w i l l s p o n t a n e o u s l y form such s t r u c t u r e s when a g i t a t e d w i t h an aqueous phase. They can be e i t h e r u n i l a m e l l a r , t h a t i s composed of a s i n g l e b i l a y e r w i t h an e n c l o s e d aqueous phase, or m u l t i - l a m e l l a r , i n which t h e r e are m u l t i p l e b i l a y e r s e n c l o s i n g the aqueous phase. The incorporated aqueous phase can have a d i f f e r e n t c o m p o s i t i o n from the s u s p e n s i o n medium. S e n s i t i z e r - Membrane I n t e r a c t i o n s The a b i l i t y of s e n s i t i z e r s to generate s i n g l e t oxygen i n membranes can be i n f l u e n c e d by i n t e r a c t i o n of the s e n s i t i z e r w i t h membrane components. B i n d i n g of s e n s i t i z e r to s u b s t r a t e has been shown to f a v o r Type I r e a c t i o n s i n homogenous s o l u t i o n s . Modification in which the s e n s i t i z e r i s p h y s i c a l l y s e p a r a t e d from the t a r g e t suggests a Type I I r e a c t i o n . The s e n s i t i z e r s to be c o n s i d e r e d here include the h a l o g e n a t e d f l u o r e s c e i n d e r i v a t i v e s ( x a n t h e n e s ) , the p o r p h y r i n s and merocyanine-540. These were s e l e c t e d because they are w i d e l y


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Intrinsic Anion Transport ^Proteins Protein |r


Ankyrin

, 6 7 ). However, a few s t u d i e s have shown significant i n t e r a c t i o n of the membrane w i t h p e n e t r a t i n g singlet



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F i g u r e 5. Diagram of s i n g l e t oxygen r e a c t i o n s i n a m i c e l l a r system. S i n g l e t oxygen g e n e r a t e d by p h o t o e x c i t e d pyrene can d i f f u s e out of the m i c e l l e i n which i t was produced. Three competing pathways e x i s t with d i f f e r i n g rate constants. Spontaneous d e e x c i t a t i o n to the ground s t a t e , k^, quenching by empty m i c e l l e s , kq, and e n t r y i n t o a DPBF-containmg m i c e l l e , k . B l e a c h i n g of DPBF by s i n g l e t oxygen i s f o l l o w e d s p e c t r o p h o t o m e t r i c a l l y . Adapted from R e f s . 18 and 63.



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oxygen. Miyoshi and Tomita (68) found that m i c e l l e s produced quenching of s i n g l e t oxygen as e f f i c i e n t l y as a z i d e . They estimated t h a t the p r o b a b i l i t y of s i n g l e t oxygen p e n e t r a t i o n g i v e n an encounter w i t h a m i c e l l e was about 0.38 to 0.48. Gorman, £t a l . (18) e s t i m a t e d t h i s value as o n l y 0.1. Suwa, et a l . (45) demonstrated that c h o l e s t e r o l i n c o r p o r a t e d i n t o m i c e l l e s was e f f i c i e n t l y photomodified only i f s e n s i t i z e r was a l s o i n the m i c e l l e , not i f i t was d i s s o l v e d in the suspension medium. F i n a l l y J o r i and co-workers (^9) found that s e n s i t i z e r s e p a r a t e d i n m i c e l l a r s o l u t i o n from i t s t a r g e t was a b l e to modify i t only under some c o n d i t i o n s . How can these d i v e r s e r e s u l t s be r e c o n c i l e d ? C e r t a i n l y the d i f f e r e n c e s i n m i c e l l e or liposome c o m p o s i t i o n , s e n s i t i z e r employed and t a r g e t can i n f l u e n c e the results. This i s r e f l e c t e d by the r e s u l t s d e s c r i b e d above i n which s i n g l e t oxygen l i f e t i m e s were reduced by n e u t r a l but not c a t i o n i c o r a n i o n i c m i c e l l e s i n a s i n g l e study (L2) • The c o n c l u s i o n seems t o be t h a t under some c o n d i t i o n s i n simple model systems s i n g l e t oxygen may p e n e t r a t e membranes e a s i l y , but i n o t h e r other instances there can be s i g n i f i c a n t quenching of the p e n e t r a t i n g oxygen. The s i t u a t i o n i s r e m i n i s c e n t of the i s s u e of e f f e c t i v e sensitizer location. A l t h o u g h s e n s i t i z e r e x t e r n a l t o the membrane may e f f e c t m o d i f i c a t i o n through s i n g l e t oxygen g e n e r a t i o n , in biological systems membrane a s s o c i a t e d s e n s i t i z e r i s the e f f e c t i v e species. So, here a l s o , the r e a l q u e s t i o n i s what i s the p e n e t r a b i l i t y of s i n g l e t oxygen f o r b i o l o g i c a l membranes? A l l of the model systems d i s c u s s e d a r e d e v o i d of p r o t e i n s . Membrane proteins are good t a r g e t s f o r r e a c t i o n w i t h s i n g l e t oxygen. Thus, s i g n i f i c a n t reduction i n s i n g l e t oxygen c o n c e n t r a t i o n s may o c c u r as i t passes into or through p r o t e i n - c o n t a i n i n g b i o l o g i c a l membranes. No e x p e r i m e n t a l evidence i s a v a i l a b l e c o n c e r n i n g t h i s p o i n t . E f f e c t s of Temperature and Membrane F l u i d i t y . Temperature e f f e c t s on membrane p h o t o m o d i f i c a t i o n appear to be d i v e r s e at f i r s t s i g h t . For photohemolysis by f l u o r e s c e i n d e r i v a t i v e s Blum, eit a l . , (70) showed almost no temperature dependence f o r the p h o t o m o d i f i c a t i o n process ( d u r i n g i l l u m i n a t i o n ) and Davson and Ponder (7^) showed that even the photodynamic l y s i s o c c u r i n g a f t e r l i g h t was r e l a t i v e l y independent of temperature. Blum and Kauzmann (72) were a b l e t o show t h a t a t severely reduced t e m p e r a t u r e s , -79 and -210 C, p h o t o h e m o l y t i c membrane m o d i f i c a t i o n was g r e a t l y reduced and a b o l i s h e d r e s p e c t i v e l y . On the o t h e r hand s e n s i t i z e r a s s o c i a t i o n w i t h the membrane varies d i r e c t l y with temperature i n the i n t e r v a l b e f o r e illumination ( P o o l e r , p e r s o n a l communication). I n yeast c e l l s p h o t o i n a c t i v a t i o n s e n s i t i z e d by t o l u i d e n e b l u e i s a c c e l e r a t e d at h i g h e r temperatures w i t h a break p o i n t at 21-22° C (73^). T h i s has been a t t r i b u t e d to a change i n membrane f l u i d i t y at the t r a n s i t i o n temperature of the membrane. Membranes have been shown t o a l t e r t h e i r dye p e r m e a b i l i t y a t the phase t r a n s i t i o n of the membrane l i p i d s ( 7 4 ) . I n liposomes a l s o there appears to be a d i f f e r e n c e i n p h o t o m o d i f i c a t i o n r a t e which i s dependent on the phase t r a n s i t i o n of the l i p i d . Suwa, e_t a l . (75) used two d i f f e r e n t l i p i d s w i t h d i f f e r e n t t r a n s i t i o n temperatures. Photomodification of c h o l e s t e r o l i n c o r p o r a t e d i n t o the liposomes was g r e a t l y i n c r e a s e d above the r e s p e c t i v e t r a n s i t i o n temperature of each type of liposome. The enhanced p h o t o m o d i f i c a t i o n was a s s o c i a t e d w i t h




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an enhanced uptake of the s e n s i t i z e r , hematoporphyrin. High c h o l e s t e r o l l e v e l s are known t o a b o l i s h phase t r a n s i t i o n s . With h i g h cholesterol l e v e l s (1:2, c h o l e s t e r o l : p h o s p h o l i p i d ) hematoporphyrin incorporation and c h o l e s t e r o l m o d i f i c a t i o n showed no abrupt a l t e r a t i o n w i t h temperature. The above f i n d i n g s are most c o n s i s t e n t w i t h a temperature dependence of s e n s i t i z e r a s s o c i a t i o n w i t h the membrane. I n most s t u d i e s i n which temperature was not v a r i e d u n t i l the time of i l l u m i n a t i o n or a f t e r , no temperature dependence was seen. When p r e illumination i n c u b a t i o n occured at d i f f e r e n t temperatures the temperature dependence was d e t e c t e d . Suwa, ejt a l . (75^), w h i l e r e c o g n i z i n g the importance of s e n s i t i z e r a s s o c i a t i o n proposed that t h i s c o u l d not e n t i r e l y account f o r the observed temperature dependence. They f e l t that i n a d d i t i o n to f a c i l i t a t i n g sensitizer a s s o c i a t i o n , the i n c r e a s e i n membrane f l u i d i t y w i t h temperature augmented p h o t o m o d i f i c a t i o n r a t e s by enhancing oxygen solubility. T h i s was based on the f i n d i n g s of Kimmich and P e t e r s who reported t h a t oxygen s o l u b i l i t y i s i n c r e a s e d about 3 - f o l d above the phase transition temperature of l e c i t h i n b i l a y e r s . Since many b i o l o g i c a l membranes do not e x h i b i t w e l l d e f i n e d phase transitions the a p p l i c a b i l i t y of t h i s o b s e r v a t i o n to c e l l membranes i s u n c e r t a i n . Summary and

Conclusions

Membrane p h o t o m o d i f i c a t i o n and s i n g l e t oxygen g e n e r a t i o n i n membranes are o b v i o u s l y d i f f e r e n t from the analogous p r o c e s s e s i n simple homogenous s o l u t i o n . Membranes are s t r u c t u r e d , c o m p a r t m e n t a l i z e d systems of l i p i d s , p r o t e i n s and c h o l e s t e r o l w i t h domains of v a r y i n g h y d r o p h o b i c i t y and r e a c t i v i t y . The i n t e r a c t i o n of s e n s i t i z e r s with the membrane can be p i v o t a l in sensitization reactions. Both h a l o g e n a t e d f l u o r e s c e i n s and p o r p h y r i n s appear to l o c a l i z e near the membrane i n t e r f a c e and are e f f e c t i v e from that l o c a t i o n . They a r e relatively i n e f f e c t i v e , f o r m o d i f i c a t i o n of b i o l o g i c a l membranes, when g e n e r a t i n g s i n g l e t oxygen i n the medium e x t e r n a l to the membrane. S i n g l e t oxygen can modify many membrane components. Singlet oxygen quantum y i e l d s may be e i t h e r i n c r e a s e d or decreased i n the membrane environment depending on the sensitizer employed. P o r p h y r i n s are d i s a g g r e g a t e d by membrane a s s o c i a t i o n and demonstrate i n c r e a s e d quantum y i e l d s . Halogenated f l u o r e s c e i n s , which show no a g g r e g a t i o n e f f e c t s , have lower quantum y i e l d s i n membranes. S i n g l e t oxygen lifetimes are i n c r e a s e d i n the membrane environment independent of the mode of g e n e r a t i o n . I t can d i f f u s e a c r o s s membrane i n t e r f a c e s but the s i g n i f i c a n c e of t h i s in biological membranes i s q u e s t i o n a b l e . Finally temperature can modulate photomodification rates, p r o b a b l y through e f f e c t s on s e n s i t i z e r a s s o c i a t i o n w i t h the membrane and p o s s i b l y by i n c r e a s e d oxygen s o l u b i l i t y above the phase t r a n s i t i o n temperature of the membrane l i p i d s . [Note: For completeness the reader s h o u l d be aware that s e n s i t i z a t i o n by p s o r a l e n s has not been c o n s i d e r e d here. Psoralens a c t by n o n - s i n g l e t oxygen mechanisms on c e l l u l a r DNA. A c r i d i n e s and r e l a t e d s e n s i t i z e r s , which a l s o a f f e c t DNA, have l i k e w i s e not been t r e a t e d . ]



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A number of q u e s t i o n s c o n c e r n i n g membrane p h o t o m o d i f i c a t i o n remain unanswered. These i n c l u d e the f o l l o w i n g . 1. ) What i s ( a r e ) the membrane t a r g e t ( s ) which a r e c r i t i c a l f o r cell killing (inactivation, lysis)? 2. ) What i s t h e most e f f e c t i v e l o c a t i o n f o rsensitizer i n b i o l o g i c a l membranes? 3. ) What a r e the t r i p l e t quantum y i e l d s f o r halogenated fluoresceins and the s i n g l e t oxygen quantum y i e l d s i n membranes? 4. ) What i s t h e l i f e t i m e o f s i n g l e t oxygen i n b i o l o g i c a l membranes? 5. ) What i s the p e n e t r a b i l i t y of singlet oxygen through b i o l o g i c a l membranes? 6. ) Can s e n s i t i z e r uptake account f o r the temperature dependence of membrane p h o t o m o d i f i c a t i o n ? In c o n c l u s i o n membranes appear to be e x c e l l e n t targets f o r photomodification. Many s e n s i t i z e r s a s s o c i a t e p r e f e r e n t i a l l y with the membrane, some generate s i n g l e t oxygen more e f f i c i e n t l y there, oxygen s o l u b i l i t y and hence oxygen c o n c e n t r a t i o n s a r e h i g h e r i n t h e membrane i n t e r i o r , and s i n g l e t oxygen l i f e t i m e s a r e l o n g e r i n the membrane i n t e r i o r . Since many o f the m o l e c u l a r components o f membranes a r e s u s c e p t i b l e t o p h o t o m o d i f i c a t i o n r e a c t i o n s , conditions strongly favor membrane m o d i f i c a t i o n . Perhaps then i t is u n d e r s t a n d a b l e , as s t a t e d a t the o u t s e t o f t h i s c h a p t e r , that membranes are so o f t e n i d e n t i f i e d as c r i t i c a l t a r g e t s i n c e l l u l a r and organism p h o t o s e n s i t i z a t i o n . Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Bellnier, D.A.; Dougherty, T . J . Photochem. Photobiol. 1982, 36, 43-47. Kessel, D. Biochem. 1977, 16, 3443-3449. Moan, J.; Pettersen, E.O.; Christensen, T. Br. J. Cancer 1979, 39, 398-407. Kohn, K . ; Kessel, D. Biochem. Pharmacol. 1979, 28, 2465-2470. Volden, G.T.; Christensen, T.; Moan, J . Photobiochem. Photobiophys. 1981, 3, 105-111. Henderson, B.W.; Bellnier, D.A.; Ziring, B.; Dougherty, T . J . Adv. Exper. Med. Biol. 1983, 160, 129-138. Ehrenberg, B.; Malik, Z . ; Nitzan, Y. Photochem. Photobiol. 1985, 41, 429-435. Singer, S . J . ; Nicolson, G.L. Science 1972, 175, 720-731. Lux, S.; Shohet, S.B. Hospital Practice 1984, 19, 77-83. Shohet, S.B.; Lux, S. Hospital Practice 1984, 19, 89-108. Gilbert, D . L . ; Ehrenstein, G. Cur. Top. Membr. Transp. 1985, 22, 407-421. Lindig, B.A.; Rodgers, M.A.J. J . Phys. Chem. 1979, 83, 16831688. Rodgers, M.A.J.; Snowden, P.T. J. Amer. Chem. Soc. 1982, 104, 5543-5545. Parker, J . G . ; Stanbro, W.D. Porphyrin Localization and Treatment of Tumors.; Alan R. Liss, Inc.: 1984; pp 259-284. Pooler, J . P . ; Valenzeno, D.P. Photochem. Photobiol. 1979, 30, 581-584.


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RECEIVED November 20, 1986


Photomodification and Singlet Oxygen Generation in Membranes

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