Toxic inhibition of smooth muscle contractility by plant-derived sesquiterpenes caused by their chemically reactive alpha-methylenebutyrolactone functions.
1. Previous studies have shown that extracts of feverfew (Tanacetum parthenium) and parthenolide, a sesquiterpene alpha-methylenebutyrolactone obtained from it, inhibit smooth muscle contractility in a time-dependent, non-specific and irreversible manner. 2. The hypothesis that this toxic effect is due specifically to the presence in the sesquiterpene lactone of the potentially reactive alpha-methylene function was tested on rabbit isolated aortic ring preparations. This was done (a) by comparing the effects of two plant-derived sesquiterpene lactones purified from yellow star thistle (Centaurea solstitialis): cynaropicrin (an alpha-methylenebutyrolactone) and solstitialin 13-acetate (lacking the alpha-methylene function), and (b) by chemically inactivating the alpha-methylene functions in cynaropicrin and parthenolide by reaction with cysteine. 3. The results show that the characteristic smooth muscle inhibitory profile is demonstrated by the two alpha-methylenebutyrolactones (parthenolide and cynaropicrin), but not by the compound lacking this functional group (solstitialin 13-acetate), or by those previously active compounds in which it has been inactivated with cysteine. 4. Thus the alpha-methylene function is critical for this aspect of the toxic pharmacological profile of the sesquiterpene butyrolactones, which are natural products widely distributed in the Compositae family of flowering plants.
Pharmacology Group, King's College, London.
A J
AJ
Hay
M
M
Hamburger
K
K
Hostettmann
J R
JR
Hoult
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry; D066298:In Vitro Techniques; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010704:Phorbols; D010944:Plants / Q000737:chemistry*; D011817:Rabbits; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*
D007783:Lactones; D010704:Phorbols; D012717:Sesquiterpenes; D010656:Phenylephrine; C003325:solstitialin; C002669:parthenolide; D003545:Cysteine; C075687:cynaropicrin