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P103 Metabolic profiling of the rat liver after chronic ingestion of α-naphthylisothiocyanate using in vivo and ex vivo magnetic resonance spectroscopy
  1. B S Solanky1,
  2. G J Sanchez-Canon1,
  3. J F L Cobbold1,
  4. S D Taylor-Robinson1,
  5. J D Bell2,
  6. C L Scudamore3,
  7. J C Holder3,
  8. Po-Wah So4,
  9. I J Cox5
  1. 1Imperial College London, UK
  2. 2MRC Clinical Sciences Centre
  3. 3GlaxoSmithKline Pharmaceuticals
  4. 4King's College London, UK
  5. 5Institute of Hepatology Foundation for Liver Research

Abstract

Introduction Hepatobiliary injury, associated with intrahepatic cholestasis and biliary hyperplasia, is a commonly encountered adverse effect in man in response to certain drugs and toxins. Some human diseases affecting the biliary tree can be modelled in rats by ingestion of the hepatobiliary toxin, α-naphthylisothiocyanate (ANIT). The ability to detect biliary hyperplasia and associated hepatobiliary injury non-invasively, by longitudinal liver specific assessment, would be of value in the development of novel therapies and aid towards the understanding of hepatic pathophysiological processes.

Aim To investigate the use of in vivo hepatic phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) to provide potential biomarkers for hepatobiliary injury linked to biliary hyperplasia in the ANIT-fed rat model and to investigate longitudinal changes according to dose over a 2-week time period.

Method All experiments were performed in compliance with the UK Animals (Scientific Procedures) Act 1986. Chronic hepatobiliary dysfunction was investigated in rats fed a diet supplemented with ANIT at three doses (ANIT_0.025%, ANIT 0.04% and ANIT_0.05%) for 2 weeks using in vivo hepatic 31P MRS. In vivo 31P MRS data collected at baseline and weeks 1 and 2 for each of the three ANIT groups were compared to results from corresponding pair-fed controls (six groups of n=8 per group). Serum was collected for clinical chemistry and tissue for both histology and ex vivo 1H magic angle spinning (MAS) MRS after sacrifice at 2 weeks.

Results In vivo 31P MRS showed phosphodiesters (PDE), relative to total phosphorus signal (tPh), were significantly increased (p<0.05) after 1 and 2 weeks in both ANIT 0.05% and ANIT 0.04% groups relative to controls, but an increase in phosphomonesters (PME)/tPh was observed in the ANIT 0.05% group only. Clinical chemistry findings confirmed chronic liver injury to some extent at all ANIT dosages. Histological findings included a dose related increase in both severity of biliary hyperplasia and focal hepatocellular necrosis with increasing doses of ANIT. Ex vivo 1H MAS MRS findings supported the in vivo MRS findings in that the peak assigned to glycerophosphocholine and phosphocholine (GPC+PC) was relatively increased in the ANIT 0.05% and ANIT 0.04% groups (p<0.05) relative to the respective control groups.

Conclusion ANIT-induced moderate hepatobilliary dysfunction was associated with a dose dependent increase in phosphodiesters in vivo and choline-containing phosphodiesters and phosphomonoesters ex vivo. Such data suggest a role for magnetic resonance spectroscopy techniques as a non-invasive way of investigating hepatobilliary dysfunction.

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