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Liver regeneration is impaired by FK778 in partially hepatectomized rats, while supplemental uridine restores both liver growth and hepatocyte proliferation

Biglarnia, Ali-Reza LU orcid ; Lorant, Tomas ; Lee, Hyon-Soek ; Tufveson, Gunnar ; Tötsch, Martin and Malagó, Massimo (2009) In Hepatology Research 39(1). p.86-92
Abstract

AIM: The impact of mandatory immunosuppression on liver regeneration after segmental liver transplantation is of clinical importance. FK778, a novel immunosuppressant, inhibits pyrimidine biosynthesis and prevents rejection after organ transplantation in a dose-dependent manner. We investigated the effect of FK778 at a highly effective dose on liver regeneration in a small animal model.

METHODS: Inbred Lewis rats were subjected to 70% partial hepatectomy (PH) and treated with saline (n = 28), uridine (n = 16), FK778 alone (n = 28) or in combination with uridine (n = 16). FK778 was given intravenously daily at a dose of 25 mg/kg bodyweight (bw) and uridine was given daily intraperitoneally at a dose of 250 mg/kg bw. Liver... (More)

AIM: The impact of mandatory immunosuppression on liver regeneration after segmental liver transplantation is of clinical importance. FK778, a novel immunosuppressant, inhibits pyrimidine biosynthesis and prevents rejection after organ transplantation in a dose-dependent manner. We investigated the effect of FK778 at a highly effective dose on liver regeneration in a small animal model.

METHODS: Inbred Lewis rats were subjected to 70% partial hepatectomy (PH) and treated with saline (n = 28), uridine (n = 16), FK778 alone (n = 28) or in combination with uridine (n = 16). FK778 was given intravenously daily at a dose of 25 mg/kg bodyweight (bw) and uridine was given daily intraperitoneally at a dose of 250 mg/kg bw. Liver bodyweight ratio (LBR), hepatocyte proliferation index (PI), blood chemistry and morphological analysis were incorporated. PI was determined by Ki-67 immunostaining. De Ritis ratio was calculated to assess the extent of liver damage.

RESULTS: In FK778-treated animals PI was decreased at 24 h and 72 h and LBR was lower at 48 h and 72 h (P < 0.05) after the PH. In addition, morphological analysis showed confluent central lobular necrosis at 72 h in four of seven animals. Uridine supplementation restored PI, LBR and the de Ritis ratio in FK778-treated animals and no confluent necroses were observed.

CONCLUSION: FK778 is antihepatotrophic as well as antiproliferative during rat liver regeneration. Both liver growth and hepatocyte proliferation are completely restored by supplementation with uridine. In addition, supplemental uridine markedly reduces the severity of morphological abnormalities consistent with FK778 toxicity.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
Hepatology Research
volume
39
issue
1
pages
86 - 92
publisher
Wiley-Blackwell
external identifiers
  • pmid:18713276
  • scopus:58149204075
ISSN
1386-6346
DOI
10.1111/j.1872-034X.2008.00402.x
language
English
LU publication?
no
id
975c9621-da8d-4647-94a9-1d78d7980cfd
date added to LUP
2025-12-17 14:22:46
date last changed
2026-01-01 05:19:50
@article{975c9621-da8d-4647-94a9-1d78d7980cfd,
  abstract     = {{<p>AIM: The impact of mandatory immunosuppression on liver regeneration after segmental liver transplantation is of clinical importance. FK778, a novel immunosuppressant, inhibits pyrimidine biosynthesis and prevents rejection after organ transplantation in a dose-dependent manner. We investigated the effect of FK778 at a highly effective dose on liver regeneration in a small animal model.</p><p>METHODS: Inbred Lewis rats were subjected to 70% partial hepatectomy (PH) and treated with saline (n = 28), uridine (n = 16), FK778 alone (n = 28) or in combination with uridine (n = 16). FK778 was given intravenously daily at a dose of 25 mg/kg bodyweight (bw) and uridine was given daily intraperitoneally at a dose of 250 mg/kg bw. Liver bodyweight ratio (LBR), hepatocyte proliferation index (PI), blood chemistry and morphological analysis were incorporated. PI was determined by Ki-67 immunostaining. De Ritis ratio was calculated to assess the extent of liver damage.</p><p>RESULTS: In FK778-treated animals PI was decreased at 24 h and 72 h and LBR was lower at 48 h and 72 h (P &lt; 0.05) after the PH. In addition, morphological analysis showed confluent central lobular necrosis at 72 h in four of seven animals. Uridine supplementation restored PI, LBR and the de Ritis ratio in FK778-treated animals and no confluent necroses were observed.</p><p>CONCLUSION: FK778 is antihepatotrophic as well as antiproliferative during rat liver regeneration. Both liver growth and hepatocyte proliferation are completely restored by supplementation with uridine. In addition, supplemental uridine markedly reduces the severity of morphological abnormalities consistent with FK778 toxicity.</p>}},
  author       = {{Biglarnia, Ali-Reza and Lorant, Tomas and Lee, Hyon-Soek and Tufveson, Gunnar and Tötsch, Martin and Malagó, Massimo}},
  issn         = {{1386-6346}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{86--92}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Hepatology Research}},
  title        = {{Liver regeneration is impaired by FK778 in partially hepatectomized rats, while supplemental uridine restores both liver growth and hepatocyte proliferation}},
  url          = {{http://dx.doi.org/10.1111/j.1872-034X.2008.00402.x}},
  doi          = {{10.1111/j.1872-034X.2008.00402.x}},
  volume       = {{39}},
  year         = {{2009}},
}