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Open Access Highly Accessed Research article

Uridine prevents tamoxifen-induced liver lipid droplet accumulation

Thuc T Le123*, Yasuyo Urasaki123 and Giuseppe Pizzorno12*

Author Affiliations

1 Nevada Cancer Institute, One Breakthrough Way, Las Vegas, NV 89135, USA

2 Desert Research Institute, 10530 Discovery Drive, Las Vegas, NV 89135, USA

3 Roseman University of Health Sciences, 11 Sunset Way, Henderson NV 89014, USA

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BMC Pharmacology and Toxicology 2014, 15:27  doi:10.1186/2050-6511-15-27

Published: 23 May 2014

Abstract

Background

Tamoxifen, an agonist of estrogen receptor, is widely prescribed for the prevention and long-term treatment of breast cancer. A side effect of tamoxifen is fatty liver, which increases the risk for non-alcoholic fatty liver disease. Prevention of tamoxifen-induced fatty liver has the potential to improve the safety of long-term tamoxifen usage.

Methods

Uridine, a pyrimidine nucleoside with reported protective effects against drug-induced fatty liver, was co-administered with tamoxifen in C57BL/6J mice. Liver lipid levels were evaluated with lipid visualization using coherent anti-Stokes Raman scatting (CARS) microscopy, biochemical assay measurement of triacylglyceride (TAG), and liquid chromatography coupled with mass spectrometry (LC-MS) measurement of membrane phospholipid. Blood TAG and cholesterol levels were measured. Mitochondrial respiration of primary hepatocytes in the presence of tamoxifen and/or uridine was evaluated by measuring oxygen consumption rate with an extracellular flux analyzer. Liver protein lysine acetylation profiles were evaluated with 1D and 2D Western blots. In addition, the relationship between endogenous uridine levels, fatty liver, and tamoxifen administration was evaluated in transgenic mice UPase1−/−and UPase1-TG.

Results

Uridine co-administration prevented tamoxifen-induced liver lipid droplet accumulation in mice. The most prominent effect of uridine co-administration with tamoxifen was the stimulation of liver membrane phospholipid biosynthesis. Uridine had no protective effect against tamoxifen-induced impairment to mitochondrial respiration of primary hepatocytes or liver TAG and cholesterol export. Uridine had no effect on tamoxifen-induced changes to liver protein acetylation profile. Transgenic mice UPase1−/−with increased pyrimidine salvage activity were protected against tamoxifen-induced liver lipid droplet accumulation. In contrast, UPase1-TG mice with increased pyrimidine catabolism activity had intrinsic liver lipid droplet accumulation, which was aggravated following tamoxifen administration.

Conclusion

Uridine co-administration was effective at preventing tamoxifen-induced liver lipid droplet accumulation. The ability of uridine to prevent tamoxifen-induced fatty liver appeared to depend on the pyrimidine salvage pathway, which promotes biosynthesis of membrane phospholipid.

Keywords:
Coherent anti-Stokes Raman scattering microscopy; Drug-induced fatty liver; Lipidomics; Membrane phospholipid; Mitochondrial respiration; Protein lysine acetylation; Pyrimidine; Tamoxifen; Triacylglyceride; Uridine phosphorylase