Inactivation of the Cytotoxic Activity of Repin, a Sesquiterpene Lactone from Centaurea repens

• Published in: Chemical research in toxicology Vol. 17; no. 9; pp. 1170 - 1176
• Main Authors: Tukov, Francis F, Anand, S, Gadepalli, Rama Sarma V. S, Gunatilaka, A. A. Leslie, Matthews, John C, Rimoldi, John M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.09.2004
• Subjects: Animals; Cell Survival - drug effects; Centaurea - chemistry; Centaurea - toxicity; Centaurea repens; Centaurea solstitialis; Cytotoxins - chemistry; Cytotoxins - toxicity; Dose-Response Relationship, Drug; PC12 Cells - drug effects; Rats; Sesquiterpenes - chemistry; Sesquiterpenes - toxicity; Structure-Activity Relationship; Toxicity Tests
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx049864e

Prolonged ingestion of Yellow Starthistle (Centaurea solstitialis) and Russian Knapweed (Centaurea repens) by horses has been shown to result in a fatal neurodegenerative disorder called equine nigropallidal encephalomalacia (ENE). Bioassay-guided fractionation of extracts from Centaurea species using the PC12 cell line have led to the identification of one of several putative agents, which may contribute to ENE, namely, the sesquiterpene lactone (SQL) repin (1), previously linked to ENE due to its abundance in C. repens. To characterize the molecular basis of repin-induced neurotoxicity, the present study was designed to identify reactive functional groups that may contribute overall to its toxicity. The reaction of repin (1) with glutathione (GSH) led to the exclusive addition of GSH to the α-methylenebutyrolactone affording a GSH conjugate (3b) that lacked toxicity in the PC12 cell assay, while selective reduction of the α-methylenebutyrolactone double bond of 1 also resulted in an analogue (2) that was devoid of toxicity relative to the parent compound. Unlike repin, analogue 2 failed to decrease cellular dopamine levels in PC12 cells, further substantiating the requirement of the α-methylenebutyrolactone group. Results from this study are suggestive that GSH depletion by the SQL repin may be a primary event in the etiology of ENE, increasing the susceptibility to oxidative damage.