Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans

Figure 1

Overview of mechanisms of DILI. Figure extracted from Godoy et al. [21]. (1) Detoxification: conjugation with glutathione. (2) Altered calcium homeostasis. (3) Reactive metabolites may bind to transport pumps or actin around the bile canaliculi preventing bile export. (4) Reactive metabolites binding to mitochondrial proteins may reduce ATP formation, produce ROS, and open the MPTP causing apoptosis. (5) Immune stimulation via the hapten or prohapten mechanisms leading to either humoral (B cell) or cell-mediated (T cell) reactions. (6) Immune activation (PI mechanism with parent drug). (7) TNF receptor sensitivity may be heightened increasing responsiveness to TNF, leading to apoptosis. For more details, please refer to Godoy et al. [21]. Figure reproduced with permission.