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.

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

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Aryl-aryl bond formation one century after the discovery of the Ullmann reaction.

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

How many types of calcium channels exist in neurones? This question is fundamental to understanding how calcium entry contributes to diverse neuronal functions such as transmitter release, neurite extension, spike initiation and rhythmic firing. There is considerable evidence for the presence of more than one type of Ca conductance in neurones and other cells. However, little is known about single-channel properties of diverse neuronal Ca channels, or their responsiveness to dihydropyridines, compounds widely used as labels in Ca channel purification. Here we report evidence for the coexistence of three types of Ca channel in sensory neurones of the chick dorsal root ganglion. In addition to a large conductance channel that contributes long-lasting current at strong depolarizations (L), and a relatively tiny conductance that underlies a transient current activated at weak depolarizations (T), we find a third type of unitary activity (N) that is neither T nor L. N-type Ca channels require strongly negative potentials for complete removal of inactivation (unlike L) and strong depolarizations for activation (unlike T). The dihydropyridine Ca agonist Bay K 8644 strongly increases the opening probability of L-, but not T- or N-type channels.

Three types of neuronal calcium channel with different calcium agonist sensitivity.

NEUROTRANSMITTER released from neurons is known to signal to neighbouring neurons and glia1–3 Here we demonstrate an additional signalling pathway in which glutamate is released from astrocytes and causes an NMDA (N-methyl-d-aspartate) receptor-mediated increase in neuronal calcium. Internal calcium was elevated and glutamate release stimulated by application of the neuro-ligand bradykinin to cultured astrocytes. Elevation of astrocyte internal calcium was also sufficient to induce glutamate release. To determine whether this released glutamate signals to neurons, we studied astrocyte–neuron co-cultures. Bradykinin significantly increased calcium levels in neurons co-cultured with astrocytes, but not in solitary neurons. The glutamate receptor antagonists d-2-amino-5-phosphonopentanoic acid and d-glutamylglycine prevented bradykinin-induced neuronal calcium elevation. When single astrocytes were directly stimulated to increase internal calcium and release glutamate, calcium levels of adjacent neurons were increased; this increase could be blocked by d-glutamylglycine. Thus, astrocytes regulate neuronal calcium levels through the calcium-dependent release of glutamate.

Glutamate-mediated astrocyte-neuron signalling.

A chemically heterogeneous group of compounds, the Ca++ channel antagonists, which includes verapamil, diltiazem and nifedipine inhibits excitation-contraction coupling in smooth and cardiac muscle by blocking Ca+ entry at a specific class of Ca++ channels. The binding of the nifedipine analog, [3H]nitrendipine, to a microsomal fraction from guinea-pig longitudinal smooth muscle has been characterized. Specific binding was saturable, linear with protein concentration and reversible. The apparent equilibrium dissociation constant was 1.63 +/- 0.06 X 10(-10)M and the maximum site density was 1.13 +/- 0.03 pmol/mg of protein determined from Scatchard analysis of equilibrium binding at 25 degrees C. Inhibition of binding was specific and stereoselective for Ca++ channel antagonist drugs and was unaffected by a variety of receptor active ligands. Correlations between binding and inhibition of mechanical response to methylfurmethide- and K+-stimulation in a series of nifedipine analogs were determined. A 1:1 correlation was found for the K+ tonic response, but for the phasic component of the K+ response and for both components of the methylfurmethide response the antagonists were more active as inhibitors of [3H]nitrendipine binding than as inhibitors of mechanical response. [3H]Nitrendipine binding was sensitive to other Ca++ channel antagonists including verapamil, D-600, diltiazem, flunarizine, lidoflazine and bepridil. Interaction with these agents suggests, consistent with previous reports, that more than one binding site for Ca++ antagonists exists. A variety of inorganic divalent and trivalent cations (Mn++, Co++, Ni++, Pb++, UO2++, Zn++, Cd++, Cu++, Tm+++ and La+++) inhibit specific [3H]nitrendipine binding. The data suggest that [3H]nitrendipine binding in smooth muscle is to a site which mediates the pharmacologic response.

Characterization of binding of the Ca++ channel antagonist, [3H]nitrendipine, to guinea-pig ileal smooth muscle.

Administration of certain fluoroquinolone antibacterials has been associated with prolongation of the QT interval on the electrocardiogram and, on rare occasions, ventricular arrhythmia. Blockade of the human cardiac K+ channel HERG often underlies such clinical findings. Therefore, we examined a series of seven fluoroquinolones for their ability to interact with this channel. Using patch-clamp electrophysiology, we found that all of the drugs tested inhibited HERG channel currents, but with widely differing potencies. Sparfloxacin was the most potent compound, displaying an IC50 value of 18 microM, whereas ofloxacin was the least potent compound, with an IC50 value of 1420 microM. Other IC50 values were as follows: grepafloxacin, 50 microM; moxifloxacin, 129 microM; gatifloxacin, 130 microM; levofloxacin, 915 microM; and ciprofloxacin, 966 microM. Block of HERG by sparfloxacin displayed a positive voltage dependence. In contrast to HERG, the KvLQT1/minK K+ channel was not a target for block by the fluoroquinolones. These results provide a mechanism for the QT prolongation observed clinically with administration of sparfloxacin and certain other fluoroquinolones because free plasma levels of these drugs after therapeutic doses approximate those concentrations that inhibit HERG channel current. In the cases of levofloxacin, ciprofloxacin, and ofloxacin, inhibition of HERG occurs at concentrations much greater than those observed clinically. The data indicate that clinically relevant HERG channel inhibition is not a class effect of the fluoroquinolone antibacterials but is highly dependent upon specific substitutions within this series of compounds. HERG channel affinity should be an important criterion for the development of newer fluoroquinolones.

Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG.

Review of Ca 2+ channel: mecanism of action, structure, pharmacology, regulation. Structure activity relationships of the 1,4-dihydropyridines

Ca2+ channel ligands: Structure‐function relationships of the 1,4‐dihydropyridines

Calcium channel antagonists: Clinical uses—Past, present and future

1. The 1,4-dihydropyridine nucleus serves as the scaffold for important cardiovascular drugs—calcium antagonists—including nifedipine, nitrendipine, amlodipine, and nisoldipine, which exert their antihypertensive and antianginal actions through actions at voltage-gated calcium channels of the CaV1 (L-type) class.

David J. Triggle

Papers

Characterization of binding of the Ca++ channel antagonist, [3H]nitrendipine, to guinea-pig ileal smooth muscle.

Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG.

Ca2+ channel ligands: Structure‐function relationships of the 1,4‐dihydropyridines

Calcium channel antagonists: Clinical uses—Past, present and future

1,4-dihydropyridines as calcium channel ligands and privileged structures