title: Herbicidal effects of statin pharmaceuticals in Lemna gibba.
abstract: Statin pharmaceuticals, heavily prescribed in the treatment of hypercholesterolemia, are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR). In plants, these compounds also inhibit HMGR, which regulates cytosolic isoprenoid biosynthesis in the mevalonic acid (MVA) pathway. Phytotoxicity was evaluated in the higher aquatic plant Lemna gibba exposed to atorvastatin and lovastatin for 7-days by measuring the concentrations of sterols and ubiquinone; products downstream in the MVA pathway. The efficiency of the parallel and unaffected methylerythritol phosphate pathway (MEP) was also evaluated by measuring the end product, plastoquinone. Statin treatment caused an accumulation of plastoquinone, and unexpectedly, ubiquinone, an artifact likely due to metabolite sharing from the plastidial MEP pathway. Statins were, however, highly phytotoxic to L. gibba and HPLC-UV analysis of plant extracts showed significantly decreased concentrations of both stigmasterol and beta-sitosterol, which are critical components of plant membranes and regulate morphogenesis and development. EC10 values for atorvastatin and lovastatin were as small as 26.1 and 32.8 microg/L, respectively. However, hazard quotients indicated that statins present little risk to the model higher aquatic plant Lemna gibba at environmentally relevant concentrations, even though pathway-specific endpoints were 2-3 times more sensitive than traditional gross morphological endpoints typically used in risk assessment.
authors.affiliation: Department of Environmental Biology, University of Guelph, Ontario, Canada. rbrain01@uoguelph.ca
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brain
authors.forename: Tamara S
authors.initials: TS
authors.lastname: Reitsma
authors.forename: Linda I
authors.initials: LI
authors.lastname: Lissemore
authors.forename: Ketut
authors.initials: K
authors.lastname: Bestari
authors.forename: Paul K
authors.initials: PK
authors.lastname: Sibley
authors.forename: Keith R
authors.initials: KR
authors.lastname: Solomon
mesh_terms: D000069059:Atorvastatin; D002851:Chromatography, High Pressure Liquid; D006538:Heptanoic Acids / Q000494:pharmacology*; D006540:Herbicides / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000032:analysis*; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000737:chemistry; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000032:analysis*; D010944:Plants / Q000378:metabolism*; D010971:Plastoquinone / Q000032:analysis; D011758:Pyrroles / Q000494:pharmacology*; D018570:Risk Assessment; D012855:Sitosterols / Q000032:analysis; D013261:Sterols / Q000032:analysis / Q000737:chemistry; D014451:Ubiquinone / Q000032:analysis; D014466:Ultraviolet Rays
chemical_list: D006538:Heptanoic Acids; D006540:Herbicides; D004364:Pharmaceutical Preparations; D011758:Pyrroles; D012855:Sitosterols; D013261:Sterols; D014451:Ubiquinone; C025473:gamma-sitosterol; D008148:Lovastatin; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D010971:Plastoquinone; D008798:Mevalonic Acid