Original articles
Gundala Venkata Naveen Kumar, Keito Hoshitsuki, Sanjay Rathod, Manda J. Ramsey, Lauren Kokai, Erin E. Kershaw, Wen Xie, Christian A. Fernandez. Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3779-3790

Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice
Gundala Venkata Naveen Kumara, Keito Hoshitsukia,b, Sanjay Rathoda, Manda J. Ramseya, Lauren Kokaic, Erin E. Kershawd, Wen Xiea, Christian A. Fernandeza
a. Department of Pharmaceutical Sciences and Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261, USA;
b. Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;
c. Department of Plastic Surgery, University of Pittsburgh and the McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15261, USA;
d. University of Pittsburgh, Division of Endocrinology, Department of Medicine, Pittsburgh, PA 15261, USA
Abstract:
PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.
Key words:    Liver injury    Leukemia    Asparaginase    Lipolysis    Adverse drug reaction    Adipose tissue    Hepatic steatosis    Amino acid response   
Received: 2021-10-19     Revised: 2021-11-24
DOI: 10.1016/j.apsb.2021.11.022
Funds: This work was supported by the National Institutes of Health grants CA216815 and TL1TR001858 (USA), the Pittsburgh Liver Research Center, Rho Chi Society and American Foundation for Pharmaceutical Education (USA), and the University of Pittsburgh School of Pharmacy (USA).
Corresponding author: Christian A. Fernandez,E-mail:chf63@pitt.edu     Email:chf63@pitt.edu
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Gundala Venkata Naveen Kumar
Keito Hoshitsuki
Sanjay Rathod
Manda J. Ramsey
Lauren Kokai
Erin E. Kershaw
Wen Xie
Christian A. Fernandez

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