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Disrupted hepatic pentose phosphate pathway directly participates in and indirectly promotes CYP3A reduction: A new strategy for CYP3A‐mediated drug hepatotoxicity
Author(s) -
Liu Jiali,
Jin Xiaoliang,
Zhou Fang,
Chen Hongzhu,
Wang Wenjie,
Liu Yan,
Wang Guangji,
Hao Kun,
Zhang Jingwei
Publication year - 2020
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14916
Subject(s) - cyp3a , pharmacology , in vivo , pentose phosphate pathway , biology , menadione , cancer research , endocrinology , enzyme , glycolysis , biochemistry , metabolism , cytochrome p450 , microbiology and biotechnology
Background and Purpose 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 Results 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.