Abstract

Several studies in South Africa indicate that as many as one in 12 individuals are admitted to hospital because of adverse drug reactions. The extraordinary genetic diversity across the continent, in combination with a unique disease burden justifies the need to develop interventions which can support health care practitioners in stratifying best treatment options for each patient. However, in vitro models such as primary human hepatocytes from individuals of African descent have been limited by accessibility. Thus, much emphasis has been placed on the potential of induced pluripotent stem cells and their differentiation capability. Despite many advances in improving the overall hepatocyte phenotype, deriving functional liver metabolizing enzymes which are comparable to their primary counterparts remains elusive, thus limiting their widespread use in pharmacovigilance programmes, especially in Africa. In our research we’ve sought to establish robust and reproducible hepatocyte-like cells using samples harbouring metabolism gene alleles unique to or prevalent in the local population. Similar to that observed by several published protocols, switching from 2D to 3D model systems led to a robust improvement in the gene expression of key xenobiotic metabolism genes. Despite improved metabolism activity as measured by proxy (luciferase assays), evaluating phase I metabolism, using LC-MS/MS, has revealed the competence of our model(s) to metabolize only one CYP450 probe drug, and has not demonstrated the metabolism of substrates specific for other CYP450 enzymes which are essential to the prediction of important African metabolism genes. However, our genetic screening has revealed an extraordinary diversity of rare, or unique genetic variants in key phase I metabolism genes linked to critical pharmaceutical compounds of relevance to the health burden of the region. To sum, we outline our current strategies to establish more physiologically relevant Afro-centric pharmacovigilance cellular models.