Herbicidal Effects of Statin Pharmaceuticals inLemna 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.

Structural responses of Daucus carota root-organ cultures and the arbuscular mycorrhizal fungus, Glomus intraradices, to 12 pharmaceuticals

“…EC 50 s for wet weight for sulfamethoxazole, levofloxacin, and chlortetracycline were 81, 185, 219 lg l À1 , respectively (Brain et al, 2004). Atorvastatin produced a wet weight EC 50 of 135 lg l À1 for L. gibba (Brain et al, 2006). The EC 50 s for these different plants were in the same rank and within an order of magnitude of each other, suggesting that the root-organ cultures exhibit a predictive and reliable response when the pharmaceutical does not specifically target part of the photosynthetic process.…”

“…Each dataset was subjected to six different reparameterized negative-response regression models which have been previously described (Brain et al, 2006;Environment Canada, 2005). The six models were derived from linear, exponential, logistic (3-parameter), logistic (4-parameter), gompertz, and hormetic concentration-response curves.…”

Human Pharmaceuticals in the Aquatic Environment: A Review of Recent Toxicological Studies and Considerations for Toxicity Testing

“…One such probabilistic modeling approach is to use chemical toxicity distributions. These have been utilized to predict antibiotic concentrations of concern in model aquatic plant species ( Brain et al 2006a, b ) , to compare the sensitivity of various in vitro and in vivo models of estrogenic activity (Dobbins et al 2008 ) , and to predict the acute and chronic toxicity of parabens to fi sh and cladocerans ) . Probabilistic Pharmaceutical Distributions (PPDs), a term coined for chemical toxicity distributions performed on pharmaceuticals that comprise multiple chemical classes and modes of action, has recently been proposed as a screening approach for identifying pharmaceuticals that have potential ecological risk.…”

Risks of agricultural pharmaceuticals in surface water systems and soils

“…Treatment of microcosms for 35 d with a mixture of atorvastatin, acetaminophen, caffeine, sulfamethoxazole, carbamazepine, levofloxacin, sertraline, and trimethoprim) at total molar concentrations of 0, 0.044, 0.608, 2.66, and 24.5 µmol/L showed concentration-dependent effects on growth of L. gibba and M. spicatum, with EC25s of 0.5 and 0.6 µmol/L, respectively. Effects on plants were attributed to the combined response to levofloxacin (a DNAgyrase inhibitor) and atorvastatin a lipid-reducing drug used in humans that also inhibits an analogous target in plants, 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) (37). These effects were observed at concentrations 10 to 100-fold greater than measured or predicted environmental concentrations.…”