de Barros Pereira, IM; (2014) Investigation of Biomarkers of Hepatic and Renal Toxicity in the Han Wistar Rat. Doctoral thesis , UCL (University College London).

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Abstract

The aim of this project was to identify urinary markers of hepatic and renal toxicity in the male Hanover-Wistar rat; acute and chronic injury models were developed by administration of CCl4. Nephrotoxicity was induced by administration of HCBD. In an acute dose study, CCl4-induced nephrotoxicity occurred above 2.0 mL/kg CCl4. To avoid kidney injury, 2.0 mL/kg CCl4 was chosen as the optimal dose. 1H NMR revealed many changes to the urinary metabolome following CCl4-induced liver injury including an increase in the resonances of taurine, creatine and formate and a decrease in hippurate and creatinine. Protein and gene expression markers were investigated in a HCBD-model of nephrotoxicity. Urinary α-GST, KIM-1 and albumin were the most sensitive biomarkers of proximal tubular injury. These markers could be used to detect unwanted kidney injury in future CCl4 hepatic studies. In a time course study, maximal liver injury from CCl4 was reached 24-48 hours post-dosing. Urinary metabolites followed the same trend and levels increased during the first 18-24 hours post-dosing. After 24 hours, there was a tendency for metabolites to return to control levels. A chronic model of CCl4-induced liver fibrosis was developed by dosing animals 3 times a week for 6 weeks to investigate the potential for reversibility and changes in urinary metabolites. After 6 weeks of CCl4-administration there was development of fibrous structures in the liver parenchyma followed by slight regeneration during the recovery period. Urinary metabolites that best reflected the development of fibrosis were creatinine, citrate and succinate. Taurine and hippurate may be useful for showing regenerative changes. In this project, we developed a good rat model of fibrosis which showed potential to reverse. 1H NMR analysis allowed characterisation of urinary metabolite changes in acute and chronic studies. Some of these metabolites have potential to be urinary markers for hepatic fibrosis.

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