The characterization of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) in rainbow trout (Oncorhynchus mykiss) and the effect of statin drugs on HMGCoAR

The presence of pharmaceuticals in the aquatic environment is a growing area of concern. The objective of this thesis was to examine the effects of statin drugs, a class of pharmaceuticals prescribed to lower endogenous cholesterol production by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR), in the rainbow trout Oncorhynchus mykiss. The study also aimed to provide some insight into mechanisms governing the control of HMGCoAR in fish. Two statin drugs were used in this study, cerivastatin (CVT) and atorvastatin (AVT). Cerivastatin inhibited hepatic microsomal and brain homogenate HMGCoAR activities when incubated in vitro and following an in vivo intra-peritoneal injection. Atorvastatin reduced HMGCoAR activity in vitro following incubation with liver microsomes and brain homogenates. Fasting trout for 14 days resulted in a significant decrease in plasma cholesterol and glucose levels compared with the fed-controls. A significant decrease was observed in brain homogenates prepared from fish fasted for 14 days and re-fed for 7 days. Phosphorylation is an important regulator of mammalian HMGCoAR activities. In trout a significant decrease in HMGCoAR activity was observed when liver microsomes were incubated in a buffer that should stimulate AMPK. Two HMGCoAR subtypes were found in rainbow trout. HMGCoAR-1 mRNA is present in higher quantities than HMGCoAR-2 however HMGCoAR-1 is located in a limited number of tissues. HMGCoAR-2 mRNA appeared in all tissues assessed. The results of this thesis indicate that HMGCoAR shares some similar control mechanisms with mammals. These results also demonstrate that statin drugs in the aquatic environment have the potential to disrupt HMGCoAR in fish