Vol. 52, Issue 4, 673-751, December 2000

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

Elliott Middleton, Jr., Chithan Kandaswami and Theoharis C. Theoharides¹

Chebeague Island Institute of Natural Product Research, Chebeague Island, Maryland (E.M., C.K.); and Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (T.C.T.)

I. General Aspects
    A. Introduction
    B. Synthesis
    C. Metabolism and Disposition
    D. Adverse Reactions
II. Effects on Mammalian Enzyme Systems
    A. Kinases
    B. Phospholipase A₂
    C. ATPases
    D. Lipoxygenases and Cyclooxygenases
    E. Phospholipase C
    F. Cyclic Nucleotide Phosphodiesterase
    G. Adenylate Cyclase
    H. Reverse Transcriptase
    I. HIV-1 Proteinase
    J. HIV-1 Integrase
    K. Ornithine Decarboxylase
    L. Topoisomerase
    M. Glutathione S-Transferase
    N. Epoxide Hydrolase
    O. Glyoxalase
    P. Xanthine Oxidase
    Q. Aromatase
    R. 11--Hydroxysteroid Dehydrogenase
    S. Catechol-O-methyltransferase
    T. Aldose Reductase
    U. Monoamine Oxidase (FAD-Containing)
    V. Aldo-Keto-Reductase Family of Enzymes
    W. Hyaluronidase
    X. Histidine Decarboxylase and DOPA Decarboxylase
    Y. Malate Dehydrogenase
    Z. Lactic Dehydrogenase and Pyruvate Kinase
    AA. Aldehyde and Alcohol Dehydrogenases
    BB. Amylase
    CC. RNA and DNA Polymerases
    DD. Human DNA Ligase I
    EE. Ribonuclease
    FF. Sialidase
    GG. Cytochrome P450 Systems
    HH. Elastase
    II. Nitric-Oxide Synthase
III. Modulation of the Functions of Inflammatory Cells
    A. T Lymphocytes
    B. B Lymphocytes
    C. Natural Killer Cells
    D. Macrophages and Monocytes
    E. Mast Cells and Basophils
    F. Neutrophils
    G. Eosinophils
    H. Platelets
    I. Adhesion Molecule Expression
IV. Effects of Flavonoids on Other Cells
    A. Smooth Muscle and Cardiac Muscle Cells
    B. Effects on Nerve Cells
    C. Calcium Homeostasis
V. Endocrine and Metabolic Effects
VI. Antiviral Effects
VII. Antitoxic, Hepatoprotective, and Cytoprotective Effects
VIII. Antioxidant Activity
    A. Influence of Flavonoids on Reactive Oxygen Species Production by Phagocytic Cells
    B. Effect of Flavonoids on Lipid Peroxidation and Oxyradical Production
IX. Actions in Relation to Coronary Artery Disease and Vascular Disorders
X. Flavonoid-Vitamin C Interactions
XI. Cancer-Related Properties
    A. Microbial Mutagenicity Studies
    B. Genetic Effects of Flavonoids in Mammalian Cells
    C. Mutagenicity Studies in Vivo
    D. Carcinogenicity of Flavonoids?
    E. Anticarcinogenic Effects
    F. Apoptosis and Cancer
    G. Antiproliferative Activity
    H. Differentiating Effects
    I. Adhesion/Metastasis/Angiogenesis
    J. Effect on Heat Shock Proteins
    K. Effect on Multidrug Resistance
XII. Effects on Xenobiotic Metabolism
XIII. Concluding Remarks
Acknowlegments
References

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.