Metabolic Effects of Doxorubicin on the Rat Liver Assessed With Hyperpolarized MRI and Metabolomics.

Kerstin N Timm,Dragana Savic,James A West,Jack J Miller,Julian L Griffin,Damian J Tyler,Vicky Ball

doi:10.3389/fphys.2021.782745

Abstract

Doxorubicin (DOX) is a successful chemotherapeutic widely used for the treatment of a range of cancers. However, DOX can have serious side-effects, with cardiotoxicity and hepatotoxicity being the most common events. Oxidative stress and changes in metabolism and bioenergetics are thought to be at the core of these toxicities. We have previously shown in a clinically-relevant rat model that a low DOX dose of 2 mg kg–1 week–1 for 6 weeks does not lead to cardiac functional decline or changes in cardiac carbohydrate metabolism, assessed with hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (MRS). We now set out to assess whether there are any signs of liver damage or altered liver metabolism using this subclinical model. We found no increase in plasma alanine aminotransferase (ALT) activity, a measure of liver damage, following DOX treatment in rats at any time point. We also saw no changes in liver carbohydrate metabolism, using hyperpolarized [1-13C]pyruvate MRS. However, using metabolomic analysis of liver metabolite extracts at the final time point, we found an increase in most acyl-carnitine species as well as increases in high energy phosphates, citrate and markers of oxidative stress. This may indicate early signs of steatohepatitis, with increased and decompensated fatty acid uptake and oxidation, leading to oxidative stress.

Highlights

Doxorubicin (DOX) is a widely used chemotherapeutic agent for both solid and haematological malignancies
We have previously shown in a rat model of DOX-cardiotoxicity, that high dose DOX (3 mg kg−1 for 5 weeks) leads to cardiac systolic dysfunction, which is preceded by a decrease in cardiac carbohydrate metabolism, assessed by hyperpolarized [1-13C]pyruvate MR spectroscopy (MRS)
The [1-13C]lactate signal was derived from 13C labelexchange between the endogenous lactate pool and injected hyperpolarized [1-13C]pyruvate through lactate dehydrogenase (LDH; Kettunen et al, 2010), [1-13C]bicarbonate was derived from oxidative decarboxylation of [1-13C]pyruvate through pyruvate dehydrogenase (PDH) (Schroeder et al, 2008) and [1-13C]alanine was derived through ALT activity from [113C]pyruvate

Summary

Introduction

Doxorubicin (DOX) is a widely used chemotherapeutic agent for both solid and haematological malignancies. Hepatic Metabolic Effects of Doxorubicin imaging (MRI) and MR spectroscopy (MRS) can assess cardiac metabolic fluxes in vivo both in pre-clinical models and in patients (Timm et al, 2018). We have previously shown in a rat model of DOX-cardiotoxicity, that high dose DOX (3 mg kg−1 for 5 weeks) leads to cardiac systolic dysfunction, which is preceded by a decrease in cardiac carbohydrate metabolism, assessed by hyperpolarized [1-13C]pyruvate MRS. Using a low dose of DOX (2 mg kg−1 for 6 weeks) we showed that there are no changes in cardiac carbohydrate metabolism and only mild cardiac systolic impairment, which were compensated by increased heart rate and led to normal cardiac index, a body-weighed adjusted measure of cardiac output (Timm et al, 2020)

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Results

Conclusion