Jrs. Hoult et M. Paya, PHARMACOLOGICAL AND BIOCHEMICAL ACTIONS OF SIMPLE COUMARINS - NATURAL-PRODUCTS WITH THERAPEUTIC POTENTIAL, General pharmacology, 27(4), 1996, pp. 713-722
1. More than 1300 coumarins have been identified from natural sources,
especially green plants. The pharmacological and biochemical properti
es and therapeutic applications of simple coumarins depend upon the pa
ttern of substitution. More complex related compounds based on the cou
marin nucleus include the dicoumarol/warfarin anticoagulants, aflatoxi
ns and the psoralens (photosensitizing agents). 2. Coumarin itself (1,
2-benzopyrone) has long established efficacy in slow onset long-term r
eduction of lymphoedema in man, as confirmed in recent double-blind tr
ials against elephantiasis and postmastectomy swelling of the arm. The
mechanism of action is uncertain, but may involve macrophage induced
proteolysis of oedema protein. However, coumarin has low absolute bioa
vailability in man (<5%), due to extensive first-pass hepatic conversi
on to 7-hydroxycournarin followed by glucuronidation. It may, therefor
e, be a prodrug. 3. Scoparone (6,7-dimethoxycoumarin) has been purifie
d from the hypolipidaemic Chinese herb Artemisia scoparia and shown to
reduce the proliferative responses of human peripheral mononuclear ce
lls, to relax smooth muscle, to reduce total cholesterol and triglycer
ides and to retard the characteristic pathomorphological changes in hy
percholesterolaemic diabetic rabbits. Various properties of scoparone
were suggested to account for these findings, including ability to sca
venge reactive oxygen species, inhibition of tyrosine kinases and pote
ntiation of prostaglandin generation. 4. Osthole (7-methoxy-8-[3-methy
lpent-2-enyl]coumarin) from Angelica pubescens, used also in Chinese m
edicine, causes hypotension in vivo, and inhibits platelet aggregation
and smooth muscle contraction in vitro. It may interfere with calcium
influx and with cyclic nucleotide phosphodiesterases. 5. Cloricromene
, a synthetic coumarin derivative, also possesses antithrombotic antip
latelet actions, inhibits PMN neutrophil function and causes vasodilat
ation, Some of these properties of cloricromene have been ascribed to
inhibition of arachidonate release from membrane phospholipids. 6. Sim
ple coumarins possessing ortho dihydroxy functions, such as fraxetin a
nd 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid
peroxidation and scavengers of superoxide anion radicals and of aqueou
s alkylperoxyl radicals, but may be pro-oxidant (enhancing generation
of hydroxyl radicals ) in the presence of free iron ions. These coumar
ins also inhibit the proinflammatory 5-lipoxygenase enzyme at micromol
ar concentrations. Another related coumarin, 5, 7-dihydroxy-4-methylco
umarin, is of special interest as it inhibits lipid peroxidation, and
scavenges alkylperoxyl and superoxide radicals. Unlike most other simp
le coumarins studied, 5,7-dihydroxy-4-methylcoumarin also scavenges hy
pochlorous chlorous acid, and is a potent inhibitor of cyclo-oxygenase
, but is not pro-oxidant. 7. 5,7- and 6,7-dihydroxy-4-methylcoumarin b
oth reduced the duration of ventricular fibrillation in postischaemic
reperfused isolated perfused rat hearts (in which oxygen derived free
radicals are implicated , showing that these antioxidant coumarins pos
sess beneficial properties in this pathophysiological model. 8. In vie
w of the established low toxicity, relative cheapness, presence in the
diet and occurrence in various herbal remedies of coumarins, it appea
rs prudent to evaluate their properties and applications further.