Grant: Catalyst Grant: Personalized Health Catalyst Grants

Sex differences in drug metabolism can negatively affect individual responses to drugs often leading adverse drug reactions (ADRs). Several drugs used to treat mental health disorders, have been found to have a disproportionate number of ADRs in women. A major player in drug metabolism are the superfamily of enzymes known as the cytochrome P450s (CYPs). These are mostly found in the liver and are responsible for breaking down foreign chemicals. With the advent of human gene sequencing, the field of pharmacogenomics has arisen, which promises to predict ADRs based upon an individual's CYP gene sequencing profile. Because this approach focuses on individual variability in CYP gene coding sequence, it has only proven to be only 7% effective at predicting drug responses. What is missing is a measure of CYP gene expression and enzyme function, which is difficult to perform because of the near-impossibility of procuring patient liver cells. Recently, however, methods have been developed to generate induced pluripotent stem cells (iPSCs) from an individual's blood or cheek cells, which in turn can be expanded and differentiated into liver cells. Using liver cells derived from male and female patient iPSCs, we will compare sex and hormone differences in specific CYP abundance, activity, and ability to metabolize known adverse drugs in mental health. Derrick Rancourt (UCalgary), an iPSC expert, will generate iPSC liver cells. Ayman Al-Kadi (UAlberta), a human CYP expert, will characterize CYP function from said liver cells. Doug Demetrick of Calgary Laboratory Services is an end-user of our approach. Two Alberta-based core facilities, Gene Expression Profiling and Metabolomics, will support our research. Through our approach, we hope to develop new empirical methods to better support pharmacogenomics. Our ability to study drug metabolism both male and female liver cells will enable better stratification of ADRs based upon sex.