Disrupted hepatic pentose phosphate pathway directly participates in and indirectly promotes CYP3A reduction: A new strategy for CYP3A-mediated drug hepatotoxicity

Hepatic CYP450s play an important role in drug-induced hepatotoxicity. They are altered in liver diseases and in many non-liver diseases, such as extra-hepatic tumours. Consequently, CYP450-mediated abnormal drug exposure increases the incidence and extent of hepatotoxicity. This risk is often underestimated because the mechanisms underlying decreases in hepatic CYP450s in extra-hepatic tumours remain unclear. Experimental approach: We used Balb/c nude mice with s.c. transplanted 4T1, LoVo and HepG2 tumours to model extra-hepatic tumours. Decreased levels of CYP3A were evaluated by qPCR, western blotting, and metabolic activity. LC-Q/TOF-MS and GC-MS were used in combination for analysing liver metabolomics. The contribution of the pentose phosphate pathway (PPP) to decreased CYP3A was assessed using menadione and silencing of glucose-6-phosphate dehydrogenase. Key

Hepatic CYP450s play an important role in drug-induced hepatotoxicity. They are altered in liver diseases and in many non-liver diseases, such as extra-hepatic tumours. Consequently, CYP450-mediated abnormal drug exposure increases the incidence and extent of hepatotoxicity. This risk is often underestimated because the mechanisms underlying decreases in hepatic CYP450s in extra-hepatic tumours remain unclear. Experimental approach: We used Balb/c nude mice with s.c. transplanted 4T1, LoVo and HepG2 tumours to model extra-hepatic tumours. Decreased levels of CYP3A were evaluated by qPCR, western blotting, and metabolic activity. LC-Q/TOF-MS and GC-MS were used in combination for analysing liver metabolomics. The contribution of the pentose phosphate pathway (PPP) to decreased CYP3A was assessed using menadione and silencing of glucose-6-phosphate dehydrogenase. Key

CYP3A activity was inhibited at early stages of tumour growth when no significant inflammatory response was observed. The PPP was predominately disrupted at this non-inflammatory stage. Disruption of the PPP directly inhibited CYP3A through the chk2/p53/p65 pathway at the non-inflammatory stage, but at the later inflammatory stage, it indirectly potentiated the subsequent IL-6-mediated CYP3A decrease. Recovery of the PPP with menadione at the non-inflammatory stage, reversed the decreased CYP3A. Similar reversal was obtained with the IL-6 inhibitor, tocilizumab. Such modulation of the PPP to alleviate CYP3A-mediated drug hepatotoxicity was validated with dasatinib in vivo. Conclusions and implications: PPP modulation at early, non-inflammatory stages might provide a novel and distinctive approach to manage drug hepatotoxicity mediated by decreased CYP3A.