As a medical student, Richard undertook laboratory-based research projects in pharmacology, immunology and endocrinology and these projects instilled an aspiration to pursue a joint career in research and medicine. He completed his foundation training in the East of England deanery, which included an academic component in CPT. Richard moved to Liverpool in 2012 after being appointed to a NIHR academic clinical fellowship training post in CPT, based principally at the Royal Liverpool University Hospital.
During his two years as an academic clinical fellow he completed his core medical training and was involved in a large cardiovascular pharmacogenomics observational study. Through this work, Richard developed an interest in statin-associated adverse muscle disorders (myotoxicity). This led to the development of his current research project, which aims to investigate the role of a gene called P450 oxidoreductase (POR)in the development of statin-associated myotoxicity.
Statin-induced muscle toxicity: evaluating the functional effects of variability in P450 oxidoreductase.
Statins are commonly prescribed cholesterol-lowering drugs used to reduce the risk of heart attacks and strokes. Although effective, approximately 1-5% of patients experience statin-associated myotoxicity, which encompasses a spectrum of disorders from common muscle aches (mylagias) through to rare but life-threatening muscle break down (rhabdomyolysis).
The underlying causes of statin myotoxicity are poorly understood but known risk factors increase circulating statin blood levels, plausibly increasing muscle statin exposure and leading to muscle damage through ill-defined mechanisms. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of many drugs that are prescribed to patients, including several statins, and POR is necessary for CYP enzymes to function. Therefore, hypoactive POR may limit statin metabolism, increase statin blood levels and increase the risk of statin myotoxicity.
This project will investigate the functional relevance of POR by firstly using a model of POR deficiency to investigate how low POR protein levels affect the protein levels of liver drug-metabolising enzymes and transporters. Secondly, the model will be used to determine the impact of POR deficiency on statin blood levels following statin administration. Thirdly, the POR gene will be sequenced in patients who have previously suffered statin-associated rhabdomyolysis to investigate the role of POR genetic variants. Lastly, the effect(s) of identified specific POR genetic variants on statin blood levels will be investigated using data from healthy volunteers who have previously received a statin and had their blood statin levels measured.