Citrus Nutrition and Quality - American Chemical Society

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Medical and Nutritional Aspects of Citrus Bioflavonoids R. C. ROBBINS Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL 32611

In 1936 the discovery that the flavonone fraction of lemons exerted therapeutic effects on abnormal capillary permeability and fragility ushered in the era of research on role of flavonoids in the mammalian body (1). Flavonoids were proposed to be vitamins (Vitamin P) necessary to maintain the capillaries, but the vitamin concept was never substantiated and in 1950 Vickery et al. (2) recommended the term Vitamin Ρ be discontinued (term Vitamin Ρ was replaced by bioflavonoid). Subsequent research had failed to confirm early indications that abnormal capillary permeability and fragility were due to a bioflavonoid deficiency but showed these capillary defects accompanied many diseases and stresses (3,4). In 1954 Martin (4) stated "There is no disease state in which the capillaries are not detrimentally modified and converse ly there are no disease states that will not benefit by assuring proper capillary strength and integrity." In 1955 Hendrickson and Kesterson (5) listed more than 50 diseases in which bioflavonoids reportedly showed beneficial effects on capillaries or the disease process itself. However, s l i g h t and i n c o n s i s t e n t e f f e c t s along with f a i l u r e to e s t a b l i s h a mode of a c t i o n l e d to c o n t r o v e r s i e s concerning the therapeutic e f f e c t i v e n e s s of b i o f l a v o n o i d s ( 6 ) . In 1963 Freedman and M e r r i t t (7) a p t l y summarized the l i t e r a t u r e with the statement: "Following S z e n t - G y o r g y i ' s o r i g i n a l observa t i o n s on the e f f e c t of h i s Vitamin C or c i t r i n p r e p a r a t i o n s , i n v e s t i g a t i o n s by the many workers produced an experimental and c l i n i c a l l i t e r a t u r e of c o n t r a d i c t o r y thought and o b s e r v a t i o n . " However, i n recent y e a r s , evidence has accumulated on the p r e sence of h i g h l y a c t i v e methoxylated flavonoids and s t e r o i d s i n c i t r u s e x t r a c t s , and the Vitamin Ρ flavonoids have been found to e x h i b i t a trimodal a c t i o n . These f i n d i n g s have shed considerable l i g h t on the c o n t r a d i c t o r y l i t e r a t u r e . Variations i n Citrus Extracts The o r i g i n a l work of Szent-Gyorgyi and co-workers was done with a crude lemon e x t r a c t c o n t a i n i n g p r i m a r i l y h e s p e r i d i n and

0-8412-0595-7/80/47-143-043$05.00/0 © 1980 American Chemical Society In Citrus Nutrition and Quality; Nagy, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


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e r i o d i c t y o l , and the above workers had d i f f i c u l t i e s , using crude e x t r a c t s , reproducing t h e i r i n i t i a l observations (8). In 1943 work s t i l l centered on t r y i n g to i d e n t i f y the a c t i v e component i n c i t r u s e x t r a c t s . For example, Higby (9) claimed crude e x t r a c t s c o n t a i n i n g h e s p e r i d i n to be a c t i v e , while p u r i f i e d h e s p e r i d i n was i n a c t i v e , but i n 1945 Scarborough (10) reported that h e s p e r i d i n exhibited b i o l o g i c a l a c t i v i t y . In 1963 Freedman and M e r r i t t (7) f r a c t i o n a t e d a c i t r u s f l a v o n o i d complex and i d e n t i f i e d i n a d d i t i o n to h e s p e r i d i n and n a r i n g i n , a hexamethoxylated flavone ( n o b i l e t i n ) , a pentamethoxy flavone (not t a n g e r e t i n , probably s i n e n s e t i n ) and an u n i d e n t i f i e d compound with reducing p r o p e r t i e s . In con t r a s t to h e s p e r i d i n and n a r i n g i n , which e x h i b i t e d no antiinflamma t o r y a c t i v i t y , the methoxylated flavones showed strong a n t i i n f l a m matory a c t i v i t y d i s p l a y i n g a broader i n h i b i t o r y p o t e n t i a l than e i t h e r c o r t i s o n e or ACTH. Later, B i o n d i (11) and B i o n d i et a l . (12) reported the i s o l a t i o n from mixed c i t r u s b i o f l a v o n o i d s of a s t e r o i d f r a c t i o n which i n minimal doses showed c o r t i s o n e - l i k e a c t i v i t y i n the r a t and guinea p i g . Freedman and M e r r i t t (7) pointed out that the amount of t h e i r h i g h l y a c t i v e substances v a r i e d according to the methods of e x t r a c t i o n and preparation employed. Importantly, the above work showed the occurrence i n c i t r u s of small amounts of h i g h l y a c t i v e substances d i s t i n c t from the abundant vitamin Ρ f l a v o n o i d s , and the amount of these a c t i v e substances recovered with the Ρ compounds depended on the methods employed. Undoubtedly, the v a r i a b i l i t y i n b i o f l a v o n o i d prepara t i o n s from c i t r u s e x t r a c t s has contributed to the confusion i n the l i t e r a t u r e . Trimodal A c t i o n of

Bioflavonoids

In a d d i t i o n to v a r i a t i o n s i n c i t r u s e x t r a c t s , there are features of b i o f l a v o n o i d e f f e c t s on the mammalian body which may have contributed g r e a t l y to the controversy concerning f l a v o n o i d action. In 1940 Yosida (13) and i n 1955 Rinehart (14) reported e f f e c t s of h e s p e r i d i n on rheumatic f e v e r . Yosida determined the erythrocyte sedimentation r a t e (ESR) before and a f t e r i n j e c t i n g h e s p e r i d i n i n t o p a t i e n t s . In 26 sets of determinations the ESR was retarded i n 19, unchanged i n 3 and a c c e l e r a t e d i n 4 cases. Rinehart administered h e s p e r i d i n to 26 p a t i e n t s , 22 showed a decreased ESR, 1 an unchanged and 3 an increased ESR. Hence, by the usual i n t e r p r e t a t i o n that an increased ESR i n d i c a t e s patho logy, h e s p e r i d i n i n some cases showed b e n e f i c i a l e f f e c t s , i n others no e f f e c t and i n s t i l l others made the disease worse. These are indeed confusing r e s u l t s . However, l a t e r research provided data f o r a d i f f e r e n t i n t e r p r e t a t i o n of the above r e s u l t s , i . e . , h e s p e r i d i n d i d not act on the disease process but a l t e r e d the ESR by d i r e c t a c t i o n on blood c e l l s (15,16,17,18). In 1966 Robbins (15) reported that h e s p e r i d i n , n a r i n g i n and r u t i n reduced the i n t r a v a s c u l a r erythrocyte adhesion accompanying Vitamin C d e f i c i e n c y i n the guinea p i g . The above f i n d i n g s

In Citrus Nutrition and Quality; Nagy, S., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


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i n d i c a t e an e f f e c t on the ESR since increased erythrocyte aggrega t i o n i s the major f a c t o r underlying an increased ESR. This was borne out i n subsequent work i n which b i o f l a v o n o i d s added to blood i n v i t r o reduced the ESR by disaggregation of blood c e l l s (16,17, 18). Other workers reported a c t i o n of f l a v o n o i d s on blood c e l l s . In 1971 S r i n i v a s a n et a l . (19) reported that f l a v o n o i d s reduced blood c e l l aggregation. In 1973 Ten Cate et a l . (20) and i n 1975 Van Haeringen (21) reported that the semi-synthetic d e r i v a t i v e s of r u t i n 0(3-hydroxyethyl) r u t o s i d e s reduced red c e l l and p l a t e l e t aggregation. I t i s of considerable i n t e r e s t that the n a t u r a l l y o c c u r r i n g methoxylated flavones of c i t r u s were s e v e r a l f o l d more a c t i v e against blood c e l l aggregation than hydroxylated f l a v o n o i d s (16,17), and the s u b s t i t u t i o n of ethoxy groups on r u t i n g r e a t l y increased i t s a c t i v i t y against blood c e l l adhesion (17,21). When s e v e r a l b i o f l a v o n o i d s were compared f o r blood c e l l d i s aggregating a c t i v i t y against the high ESR of normal horse blood (rouleaux formatin), h e s p e r i d i n , r u t i n and q u e r c i t i n showed s l i g h t but c o n s i s t e n t r e t a r d i n g e f f e c t s on the ESR while the h i g h l y methoxylated flavones, s i n e n s e t i n , n o b i l e t i n , heptamethyoxyflavone showed s e v e r a l - f o l d greater r e t a r d i n g a c t i v i t y than the above com pounds, but n a r i n g i n c o n s i s t e n t l y a c c e l e r a t e d the ESR of horse blood (16,17,18). However, when the above b i o f l a v o n o i d s were tested _in v i t r o against the increased ESR o c c u r r i n g i n a wide v a r i e t y of human diseases, the hydroxylated and l e s s a c t i v e methoxylated b i o f l a v o n o i d s e x h i b i t e d a trimodal e f f e c t (22), i . e . , i n h i b i t e d the ESR i n some cases, showed no e f f e c t i n others and a c c e l e r a t e d the ESR i n s t i l l others; the same e f f e c t Yosida and Rinehart (13,14) observed when h e s p e r i d i n was tested _in v i v o . Hesperidin which had c o n s i s t e n t l y i n h i b i t e d , and n a r i n g i n which had c o n s i s t e n t l y a c c e l e r a t e d the ESR of horse blood, both showed a trimodal e f f e c t on the ESR of blood taken from a population of humans a f f l i c t e d with a wide v a r i e t y of diseases (22). I t should be emphasized that against one kind of erythrocyte adhesion (rou leaux formation of horse blood) the Vitamin Ρ f l a v o n o i d s were con s i s t e n t i n a c t i o n but i n c o n s i s t e n t i n a c t i o n against erythrocyte adhesion o c c u r r i n g i n a wide v a r i e t y of human diseases. Thus, the antiadhesive a c t i o n of b i o f l a v o n o i d s on erythrocytes depends on the kind of bonding between c e l l s , which according to Easty and Mercer (23), depends on the a g g l u t i n a t i n g agent. However, the hexamethoxylated f l a v o n o i d n o b i l e t i n i n s e v e r a l s t u d i e s on ery throcyte adhesion i n a wide v a r i e t y of human diseases has not been found to s i g n i f i c a n t l y a c c e l e r a t e the ESR, while s i n e n s e t i n showed s i g n i f i c a n t a c c e l e r a t i n g a c t i o n i n one study (22). The trimodal a c t i o n of b i o f l a v o n o i d s on the ESR i s not with out precedent. Dintenfass (24) found that a pyrimidine type drug of the Persantin family showed a trimodal a c t i o n on the ESR and, the a c c e l e r a t i n g e f f e c t was r e l a t e d to ABO blood type. Blood c o n t a i n i n g the A antigen showed a s t a t i s t i c a l l y s i g n i f i c a n t increase i n a c c e l e r a t e d ESR. In c o n t r a s t , b i o f l a v o n o i d s e x h i b i t e d a s i g n i f i c a n t l y higher r a t e of a c c e l e r a t e d ESR s i n blood c o n t a i n 1



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ing the Β antigen (25). Whether the b i o f l a v o n o i d s and pyrimidine drug are i n f l u e n c e d i n t h e i r response v i a the mucopolysaccharides on the c e l l membrane which determine blood type or are i n f l u e n c e d v i a a l t e r a t i o n s of plasma c o n s t i t u e n t s which may respond to blood type i s not known. Both concentrations of some plasma c o n s t i t u ents and response of blood c e l l s to plasma c o n s t i t u e n t s are i n f l u e n c e d by ABO blood type (26,27). Whether blood type antigens i n f l u e n c e adhesive bonds between erythrocytes under v a r i o u s c o n d i t i o n s of disease and s t r e s s remains to be determined. While the trimodal a c t i o n of b i o f l a v o n o i d s on blood c e l l s sheds considerable l i g h t on the nature of t h e i r a c t i o n i n the body, questions a r i s e as to what extent a c t i o n on blood c e l l s and blood rheology e x p l a i n s , i n p a r t i c u l a r , t h e i r a c t i o n on abnormal c a p i l l a r y p e r m e a b i l i t y and f r a g i l i t y and therapeutic a c t i o n i n a wide v a r i e t y of d i s e a s e s . I t should be noted that while a great number of e f f e c t s of b i o f l a v o n o i d s have been reported, the mecha nism of a c t i o n proposed are r e l a t i v e l y few, i . e . , protect a s c o r b i c a c i d against o x i d a t i o n (6,28), prevent epinephrine o x i d a t i o n (29), s t i m u l a t e the p i t u i t a r y adrenal a x i s (30), i n h i b i t a v a r i e t y of enzymes such as aldose reductase (31) or membrane bound ATP ases (32), s e l e c t i v e l y i n h i b i t phosphodiesterase (33), act i n c r o s s l i n k i n g of e l a s t i n (34), stimulate the r e t i c u l o e n d o t h e l i a l system (35), act as v a s o t r o p i c drugs (36), i n h i b i t blood c e l l aggrega t i o n (15-21) and prevent l a c t a c i d o t i c r i g i d i f i c a t i o n of the red c e l l (37); the l a t t e r two e f f e c t s i n d i c a t e a c t i o n on blood rheo logy. There i s l i t t l e evidence to support any of the above mech anisms, except the a c t i o n of b i o f l a v o n o i d s on blood rheology, as e x p l a i n i n g t h e i r e f f e c t s on abnormal c a p i l l a r y p e r m e a b i l i t y and f r a g i l i t y over a broad range of c o n d i t i o n s and b e n e f i c i a l e f f e c t s i n a wide v a r i e t y of d i s e a s e s . Blood Rheology and C a p i l l a r y

Fragility

As noted e a r l i e r , b i o f l a v o n o i d s f i r s t a t t r a c t e d a t t e n t i o n as agents that acted on abnormal c a p i l l a r y p e r m e a b i l i t y and f r a g i l i t y which was a c h a r a c t e r i s t i c f i n d i n g i n scurvy (6). However, subse quent research revealed the above c a p i l l a r y d e f e c t s were not r e s t r i c t e d to scurvy. Brown (3) reported the occurrence of a decreased c a p i l l a r y r e s i s t a n c e i n a wide v a r i e t y of d i s e a s e s . He found that i n f e c t i o n s were o f t e n present at the time when low cap i l l a r y r e s i s t a n c e was observed. Consistent with the above c a p i l l a r y defects i n disease, an increased blood c e l l aggregation and ESR i s a l s o a g e n e r a l i z e d response of the body to i n f e c t i o n and disease (38). Erythrocyte aggregates i n t e r f e r e with blood flow through the small v e s s e l s and c o n t r i b u t e to increased blood v i s c o s i t y i n l a r g e r v e s s e l s . Both phenomena cause adverse p h y s i o l o g i cal effects. For example, the blood high v i s c o s i t y syndrome i n c l u d e s f a t i g a b i l i t y , bleeding from mucous membranes, r e t i n a l v e i n enlargement and hemorrhage, n e u r o l o g i c a l abnormalities and heart f a i l u r e (39). (Several parameters can c o n t r i b u t e to the



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above c o n d i t i o n , i n a d d i t i o n to erythrocyte aggregation, e r y t h r o cyte concentration, r i g i d i t y of the erythrocytes and plasma v i s c o s i t y are involved i n blood v i s c o s i t y (40)). The r e s i s t a n c e of blood to flow reduces c a p i l l a r y p e r f u s i o n (41) with decreased r a t e s of oxygen d e l i v e r e d to the c a p i l l a r y endothelium. According to K n i s e l y et a l . (42) anoxic endothelium increases i n permeabil ity. This i s c o n s i s t e n t with the observations of Landis (43) that decreased blood flow causes a r a p i d increase i n c a p i l l a r y permea b i l i t y , but on resumption of flow, p e r m e a b i l i t y r a p i d l y returns to normal. Under two kinds of experimental c o n d i t i o n s , Robbins (15, 44) found an inverse r e l a t i o n between blood c e l l aggregation and c a p i l l a r y r e s i s t a n c e , i . e . , as blood c e l l aggregation increased c a p i l l a r y r e s i s t a n c e decreased and when aggregation decreased c a p i l l a r y r e s i s t a n c e increased. I t should be noted here that b i o f l a v o n o i d s have been proposed to be v a s o t r o p i c drugs (36), that i s , prevent l o s s of e n d o t h e l i a l c e l l s from blood v e s s e l w a l l s . O ' N e i l l (45) reported that a reduced blood flow caused a p e e l i n g of the venous endothelium. Thus, impaired blood flow appears cap able of causing abnormal c a p i l l a r y p e r m e a b i l i t y and f r a g i l i t y . Further, the trimodal a c t i o n of b i o f l a v o n o i d s on blood c e l l s o f f e r s an explanation f o r i n c o n s i s t e n t a c t i o n on the c a p i l l a r i e s . However, i t cannot be overlooked that b i o f l a v o n o i d s may a c t d i r e c t l y on the c a p i l l a r y w a l l , and the same f a c t o r s that a f f e c t r e a c t i o n of f l a v o n o i d s with blood c e l l s i n f l u e n c e s r e a c t i o n with the c a p i l l a r y membranes. I t should be noted that b i o f l a v o n o i d s bind r e v e r s i b l y to both e r y t h r o c y t e s (20) and plasma p r o t e i n s (46) . The l a t t e r a c t i o n stimulates phagocytosis i n c e r t a i n edemas (47) thereby e x e r t i n g a therapeutic e f f e c t . A l s o , note that i n the above type edemas the a c t i o n of b i o f l a v o n o i d s i s not on changes i n p e r m e a b i l i t y of the c a p i l l a r y w a l l . Therapeutic

E f f e c t s i n Disease

The a c t i o n of b i o f l a v o n o i d s on blood rheology appears to e x p l a i n t h e i r r e d u c t i o n of symptoms i n a wide v a r i e t y of d i s e a s e s . Increased blood c e l l aggregation and ESR i s a g e n e r a l i z e d response of the organism to disease and trauma (38,42) and r e p o r t e d l y causes adverse e f f e c t s such as i n t e r f e r e n c e with gaseous exchange i n t i s s u e s , accumulation of a c i d metabolites, slowed h e a l i n g of wounds, degenerative changes i n parenchymatous organs and promo t i o n of thrombosis (48). Fajers and G e l i n (49) reported that kidney, l i v e r and heart damage r e s u l t e d from severe blood c e l l aggregation. In agreement, Bergentz e t a l . (50) s t a t e d that i f e r y t h r o c y t e aggregation was severe and of long d u r a t i o n i t caused organ enlargement and i n f a r c t i o n . According to Fahraeus (51) eclampsia i s a disease of checked m i c r o c i r c u l a t i o n by red c e l l aggregates. Further, erythrocyte aggregation may i n t e r a c t with other disease processes to increase symptoms (52,53). Thus, a c t i o n of b i o f l a v o n o i d s on blood c e l l aggregation could e x p l a i n t h e i r b e n e f i c i a l e f f e c t s i n a wide v a r i e t y of d i s e a s e s .

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Perhaps at t h i s point a question should be r a i s e d as to whether a c c e l e r a t i o n of the ESR by f l a v o n o i d s i s an adverse e f f e c t . In an i n v e s t i g a t i o n of the a c c e l e r a t i v e a c t i o n of b i o f l a v o n o i d s , the ESR increased 6 to 23% depending on the f l a v o n o i d (54). Based on an average ESR of 26.8 mm per hr. i n the group of h o s p i t a l i z e d p a t i e n t s under study, the maximum average a c c e l e r a t e d ESR would reach 33.0 mm per hr. In c o n t r a s t , the ESR may reach 50 mm or more per hr. i n c e r t a i n diseases or traumas. Apparently, a c c e l e r a t i o n of the ESR i s caused by f l a v o n o i d b r i d g i n g between red c e l l s and may s e l e c t i v e l y i n v o l v e aged red c e l l s s i m i l a r to the a c t i o n of p o l y l y s i n e (55). The bridged c e l l s may then be removed from the c i r c u l a t i o n by the phagocytic c e l l s of l i v e r spleen and bone marrow (56). The phagocytic a c t i o n may continue under some cond i t i o n s to the point of anemia (56), but, with f l a v o n o i d s the a c c e l e r a t i v e a c t i o n i s associated with high red c e l l concentrat i o n s and decreases when the concentration f a l l s to about 40 volumes percent; area of maximum e f f e c t i v e t i s s u e p e r f u s i o n (57). From t h i s , i t was postulated that b i o f l a v o n o i d s might exert a r e g u l a t o r y a c t i o n on the hematocrit. However, the above a c t i o n i s not proven, but the phenomenon deserves f u r t h e r a t t e n t i o n s i n c e an elevated hematocrit r e p o r t e d l y i s associated with ischemic heart disease (58).

Intact Organism, P h y s i o l o g i c a l , Biochemical L e v e l s When b i o f l a v o n o i d s are tested against biochemical parameters such as e f f e c t on i s o l a t e d enzymes, they show c o n s i s t e n t a c t i o n . For example, q u e r c e t i n i n h i b i t s membrane-bound ATPases, and there are s e v e r a l r e p o r t s , i n agreement, that quercetin i n v i t r o i n h i b i t s ATPases from d i f f e r e n t species (32). Also, there does not appear to be controversy concerning i n h i b i t o r y a c t i o n of q u e r c e t i n on other enzymes such as aldose reductase or catechol-O-methylt r a n s f e r a s e (31,59). When we move to the p h y s i o l o g i c a l l e v e l and determine e f f e c t of b i o f l a v o n o i d s on blood c e l l adhesion, there i s c o n s i s t e n t a c t i v i t y when the compounds are tested against a p a r t i c u l a r uniform type of adhesion such as rouleaux of horse blood, but they are i n c o n s i s t e n t i n a c t i o n when tested against d i f f e r e n t kinds of bonds between aggregated c e l l s as may occur i n human diseases (22,23,42,48). The c o n t r o v e r s i e s i n the l i t e r a t u r e have a r i s e n at the l e v e l of the i n t a c t organism when b i o f l a v o n o i d s were tested against a wide v a r i e t y of diseases, v a s c u l a r abnormalities, anaphylactic shock or n o n - s p e c i f i c s t r e s s e s . For example, as noted e a r l i e r when h e s p e r i d i n was i n j e c t e d i n t o p a t i e n t s , three kinds of e f f e c t s were noted, and quercetin described above as cons i s t e n t i n a c t i o n at the biochemical l e v e l exerted a trimodal a c t i o n on erythrocyte aggregation (22). Thus, there are f a c t o r s operating i n the i n t a c t organism which modify b i o f l a v o n o i d a c t i o n .


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Bioflavonoids

Action

When a v a r i e t y of b i o f l a v o n o i d s are tested against a b i o l o g i c a l parameter, u s u a l l y s e v e r a l f l a v o n o i d s w i l l show some a c t i v i t y e x h i b i t i n g t h e i r e f f e c t s as a family of curves d i f f e r i n g s i g n i f i cantly i n a c t i v i t y . For example, over 40 f l a v o n o i d s showed some i n h i b i t o r y a c t i v i t y on aldose reductase, but quercetin and q u e r c i t r i n were most a c t i v e (31). Nineteen flavonoids were observed to i n h i b i t catechol-O-methyltransferase of human l i v e r , but those with 0-dihydroxy s t r u c t u r e at the side r i n g showed the greatest e f f e c t (59). The 0 (3-hydroxyethyl) r u t o s i d e s (HR) are semisyn t h e t i c dérivâtes of n a t u r a l l y o c c u r r i n g r u t i n . The crude preparat i o n c o n s i s t s of the f o l l o w i n g : 7-10% of 5,7,3 ,4'-tetra HR; 6065% of 7 , 3 ' , 4 ' - t r i HR; 5-8% of 5 , 7 , 4 - t r i HR; 8-12% of 7,4 d i HR and 5-8% of 4 mono HR. A mixture of mono/di HR has the greatest i n h i b i t o r y e f f e c t on p l a t e l e t aggregation (60), but the t e t r a d e r i v a t i v e has the greatest e f f e c t on erythrocyte aggregation (21). The methoxylated b i o f l a v o n o i d s of c i t r u s showed the f o l l o w ing order of a c t i v i t y (from high to low) against the high ESR of horse blood, i . e . , s i n e n s e t i n (pentamethoxy), n o b i l e t i n (hexa), heptamethoxyflavone (hepta), t a n g e r e t i n (penta), tetra-0-methyls c u t e l l a r e i n ( t e t r a ) , tri-O-methylapigenin ( t r i ) and h e s p e r i d i n (mono). S i n e n s e t i n has methoxyl groups at 5,6,7,3 ,4 whereas n o b i l e t i n (5,6,7,8,3*,4 hexamethoxyflavone) d i f f e r s by a methoxyl at the 8 p o s i t i o n and i s s i g n i f i c a n t l y (P

Citrus Nutrition and Quality - American Chemical Society

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