Food ©2007 Global Science Books Citrus Flavonoids as Functional Ingredients and Their Role in Traditional Chinese Medicine Chongwei Zhang1 • Peter Bucheli2 • Xinhua Liang1 • Yanhua Lu1* 1 State Key Laboratory of Bioreactor Engineering, New World Institute of Biotechnology, East China University of Science and Technology, Mailbox 311, Meilong Rd. No. 130, Shanghai 200237, China 2 Nestlé R&D Center Shanghai Ltd., Shanghai 201812, China Corresponding author : * [email protected] ABSTRACT Citrus flavonoid concentration in different tissues of citrus from different species around the world were compared together with citrus related traditional Chinese Medicine (TCM) ingredients. The citrus species with high flavonoid content like Citrus aurantium and the flavonoid-enriched tissues such as peel and young fruit are frequently utilized in TCM recipes for their gastric protective, antiulcer, cholesterol lowering and anti-cancer effects. Meanwhile they are commonly used as food ingredients in China. Along with the metabolism and absorption, citrus flavonoids are reviewed by their structure-activity relationships and insight is provided about how this compares with the functionalities in TCM treatments. Similar to the interaction with drug absorption, citrus flavonoid-enriched ingredients in TCM recipes usually contribute as “helper” through protecting main active components, enhancing the absorption of the main drugs, and exerting synergistic effects in the overall prescriptions. _____________________________________________________________________________________________________________ Keywords: Citrus aurantium, citrus flavonoid, Fructus Aurantii, Fructus Aurantii Immaturus, hesperidin, naringin, nobiletin, poly- methoxylated flavone, structure-activity relationship, tangeretin Abbreviations: CHI, chalcone isomerase; CHS, chalcone synthase; EBV-EA, Epstein-Barr virus early antigen; F3H, flavanone 3- hydroxylase; TCM, traditional Chinese medicine CONTENTS INTRODUCTION...................................................................................................................................................................................... 287 DISTRIBUTION........................................................................................................................................................................................ 288 Distribution in tissues............................................................................................................................................................................ 288 Citrus flavonoid biosynthesis ................................................................................................................................................................ 288 Distribution among species and TCM ................................................................................................................................................... 289 ABSORPTION AND METABOLISM....................................................................................................................................................... 290 BIOACTIVITIES AND STRUCTURE ACTIVITY RELATIONSHIP ..................................................................................................... 291 Hydroxyl group ..................................................................................................................................................................................... 291 O-methylation/methoxyl........................................................................................................................................................................ 291 The 4-oxo/4-keto function and C2-C3 double bond .............................................................................................................................. 292 Carbohydrate moieties........................................................................................................................................................................... 292 FUNCTIONALITY IN TRADITIONAL CHINESE MEDICINE ............................................................................................................. 292 Gastric protective effect......................................................................................................................................................................... 292 Antiulcer................................................................................................................................................................................................ 292 Anti-Helicobacter pylori ....................................................................................................................................................................... 293 Lowering cholesterol and anti-atherosclerosis....................................................................................................................................... 293 Anti-cancer ............................................................................................................................................................................................ 293 Interaction with food and/or drug during absorption ............................................................................................................................. 293 CONCLUSION.......................................................................................................................................................................................... 293 ACKNOWLEDGEMENTS ....................................................................................................................................................................... 293 REFERENCES........................................................................................................................................................................................... 293 APPENDIX I. CHINESE NAME LIST OF THE TCM INGREDIENTS.................................................................................................. 296 _____________________________________________________________________________________________________________ INTRODUCTION tangeretin (Fig. 1). The flavanones predominate among cit- rus flavonoids, occurring as mono and diglycosides while The wide availability and frequent consumption of citrus the methoxylated flavones occur as free aglycons (Ooghe et fruit and citrus flavonoids have raised continuous interest in al. 1994). Following the Chinese perception that food and the past decades regarding their distribution, food applica- medicine come from the same source, citrus is one of the tion and bioactivities. Naturally occurring citrus flavonoids most commonly used ingredients in traditional Chinese me- can be categorized into two groups: (1) flavanone glyco- dicine (TCM) with preparations obtained from peel, young sides such as naringin, hesperidin, neohesperidin and (2) fruit, mature fruit, flower and other tissues. These TCM polymethoxylated flavones such as nobiletin, sinensetin, ingredients are all edible food ingredients in China. Received: 2 April, 2007. Accepted: 15 August, 2007. Invited Review Food 1(2), 287-296 ©2007 Global Science Books Flavanone Glycosides OH Polymethoxylated Flavones Aglycones H3C HO O Rutinose Glycosides Neohesperidose Glycosides OH OH O OH HO O OCH OCH HO HO 3 OCH3 3 OCH OCH3 3 HO O O O O H3CO O O O OH HO O OH H3C OH OH HO HO H CO H3C 3 OH OH O OCH O O 3 OH O HO OH O Hesperetin Neohesperidin Tangeretin OH Hesperidin OH O OCH3 HO HO O OH OCH OH OH HO 3 HO O O O O O O H3CO O HO O OH OH H3C HO H3C HO H3CO HO O OH OH O OCH O OH O OH O 3 Naringin Naringenin OH Narirutin OH Sinensetin O OH HO OCH3 OH HO OH HO O OH HO O OCH3 OCH3 HO O O O O O O OH OH OH H CO O H3C 3 OH HO H3C HO OH H CO OH O HO O OH O OH O 3 OCH O Eriodictyol 3 OH Eriocitrin Neoeriocitrin O Nobiletin OH OCH3 HO OCH HO OCH O 3 3 HO HO O OCH3 OCH3 OCH3 O O HO O OH O O O H3CO O H3C HO HO H CO OCH OH O 3 3 OH O OH OH O OCH3 O Isosakuranetin Neoponcirin Poncirin Heptamethoxyflavone Fig. 1 Chemical structures of citrus flavonoids. DISTRIBUTION and they were located in the peel (del Rio et al. 1998). Distribution in tissues Citrus flavonoid biosynthesis Citrus flavonoids are widespread in plants, especially in the The flavonoid biosynthesis pathway is summarized in Fig. genus Citrus of the Rutaceae family. Their composition 2 (modified from Moriguchi et al. 2003). Chalcone syn- varies in different tissues during different stages of develop- thase (CHS) is the first enzyme in the biosynthesis of all ment. Jourdan et al. (1985) studied the distribution of classes of flavonoids in plants. It catalyzes the stepwise naringin in Citrus paradisi Macfad (cv. ‘Duncan’) by radio- condensation of three acetate residues from malonyl CoA immunoassay. They found that seed coats of ungerminated with p-coumaroyl CoA. The latter p-coumaroyl CoA is sup- seeds and young shoots had high naringin concentrations plied from the phenylpropanoid pathway, which converts whereas cotyledons and roots had very low concentrations. phenylalanine into phenolic secondary metabolites in plants. Light-grown seedlings contained nearly twice as much na- Naringenin chalcone, the product of the CHS reaction, is ringin as etiolated seedlings, and in young plants and bran- ches, the naringin content was highest in developing leaves and stem tissue. In flowers, the ovary had the highest levels 3 x malonyl-CoA 4-coumaroyl-CoA of naringin