Aspects of the chemistry and toxicology of indole-diterpenoid mycotoxins involved in tremorganic disorder of livestock.

Abstract

A method for the large-scale extraction ofNeotyphodium lolii (formerlyAcremonium lolii) infectedLolium perenne (perennial ryegrass) seed was optimized so as to efficiently obtain lolitrem B, the tremorgenic indole-diterpenoid compound thought to be the principal causative agent of the neurotoxic disorder ryegrass staggers. In a period of two weeks, 30 kg of seed could be processed yielding 125mg of pure, crystalline lolitrem B.In addition to lolitrem B, fifteen lolitrem analogues were isolated from the seed extracts and their structures determined by mass spectrometry and one- and two-dimensional NMR techniques. All but one of these analogues were previously unknown. Furthermore, three compounds related to paxilline, thought to be a precursor of lolitrem B were isolated fromPenicillium paxilli cultures.The isolation of the lolitrem and paxilline analogues provided much information on the likely pathways of lolitrem biosynthesis, and a detailed pathway is proposed. Paspaline was identified as the crucial intermediate in indole-diterpenoid biosynthesis, rather than paxilline, as previously thought. It is proposed that new endophyte incapable of biosynthesizing this substance will not produce any indole-diterpenoid tremorgens.Many of the lolitrem and paxilline derivatives isolated in the course of this study were tested for tremorgenic action in mice. These studies have identified a number of strucural features which are necessary for tremorgenic effect. Slow onset and long-duration tremors are characteristic of lolitrem compounds. For this effect, the acetal-linked isoprene unit and the stereochemistry at the A/B ring junction were identified as important. In contrast, paxilline compounds induce fast-onset and short-duration tremors. For this effect a C-13 α-orientated hydroxyl group is essential and the C-10 functionality is important. The extensive study of structure-activity relationships described in this thesis also suggests that lolitrem and paxilline compounds may exert their effects by binding to different target sites. Others have proposed that the more readily available paxilline be used as a model for the lolitrems in trials to select for animals resistant to ryegrass staggers, but the above observations suggest, however, that such an approach would not be successful.

• Authors: S C Munday-Finch
• Journal: Mycotoxin research (Mycotoxin Res) Vol. 13 Issue 2 Pg. 88 (Jun 1997) ISSN: 0178-7888 [Print] Germany
• PMID: 23604827 (Publication Type: Journal Article)