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.
Hay
A J
AJ
Pharmacology Group, King's College, London.
Hamburger
M
M
Hostettmann
K
K
Hoult
J R
JR
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