Lung injury induced by pyrrolizidine alkaloids depends on metabolism by hepatic cytochrome P450s and blood transport of
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TOXICOKINETICS AND METABOLISM
Lung injury induced by pyrrolizidine alkaloids depends on metabolism by hepatic cytochrome P450s and blood transport of reactive metabolites Yisheng He1 · Wei Lian1 · Liang Ding2 · Xiaoyu Fan2 · Jiang Ma1 · Qing‑Yu Zhang2 · Xinxin Ding2 · Ge Lin1 Received: 8 July 2020 / Accepted: 17 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Pyrrolizidine alkaloids (PAs) are common phytotoxins with both hepatotoxicity and pneumotoxicity. Hepatic cytochrome P450 enzymes are known to bioactivate PAs into reactive metabolites, which can interact with proteins to form pyrroleprotein adducts and cause intrahepatic cytotoxicity. However, the metabolic and initiation biochemical mechanisms underlying PA-induced pneumotoxicity remain unclear. To investigate the in vivo metabolism basis for PA-induced lung injury, this study used mice with conditional deletion of the cytochrome P450 reductase (Cpr) gene and resultant tissue-selective ablation of microsomal P450 enzyme activities. After oral exposure to monocrotaline (MCT), a pneumotoxic PA widely used to establish animal lung injury models, liver-specific Cpr-null (LCN) mice, but not extrahepatic Cpr-low (xh-CL) mice, had significantly lower level of pyrrole-protein adducts in the serum, liver and lungs compared with wild-type (WT) mice. While MCT-exposed LCN mice had significantly higher blood concentration of intact MCT, compared to MCT-exposed WT or xh-CL mice. Consistent with the MCT in vivo bioactivation data, MCT-induced lung injury, represented by vasculature damage, in WT and xh-CL mice but not LCN mice. Furthermore, reactive metabolites of MCT were confirmed to exist in the blood efflux from the hepatic veins of MCT-exposed rats. Our results provide the first mode-of-action evidence that hepatic P450s are essential for the bioactivation of MCT, and blood circulating reactive metabolites of MCT to the lung causes pneumotoxicity. Collectively, this study presents the scientific basis for the application of MCT in animal lung injury models, and more importantly, warrants public awareness and further investigations of lung diseases associated with exposure to not only MCT but also different PAs. Keywords Pyrrolizidine alkaloids · Monocrotaline · Lung injury · Metabolism-based pneumotoxicity · Cytochromes P450 · Cpr-null mice
Yisheng He and Wei Lian have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02921-0) contains supplementary material, which is available to authorized users. * Xinxin Ding [email protected] * Ge Lin [email protected] 1
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People’s Republic of China
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA
2
Abbreviations PAs Pyrrolizidine alkaloids MCT Monocrotaline PAH Pulmonary arterial hyperte
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