Anti-oxidant ebselen causes the resolution of experimentally induced hepatic fibrosis in rats.
BACKGROUND
Hepatic fibrosis occurs because of injury to the liver parenchyma and biliary system. We have investigated the effect of an organic selenium anti-oxidant, ebselen, in the resolution of experimentally induced hepatic fibrosis, and evaluated its effect on various paradigms involved in hepatic fibrosis.


METHODS
Following pretreatment with phenobarbitone, liver fibrosis was induced in male Fischer 344 rats by using carbon tetrachloride treatment for 10 weeks. Carbon tetrachloride-treated rats were randomly assigned into two groups: (i) no ebselen; and (ii) ebselen administered for 3 weeks following a 10-week carbon tetrachloride treatment period. Normal controls were: (i) neither carbon tetrachloride nor ebselen treated; or (ii) ebselen treated for 13 weeks. Liver sections were stained with hematoxylin and eosin, Masson trichrome and stained for reticulin by using silver impregnation. Reverse transcription-polymerase chain reaction was used to analyze the steady-state levels of gene(s) involved in: (i) hepatic fibrosis, namely, transforming growth factor-beta1, procollagen I and III, tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-13; (ii) oxidative stress, namely, cytochrome P4502E1; and (iii) preneoplastic liver foci, namely, the placental form of glutathione-S-transferase.


RESULTS
Histological staining showed that ebselen resolves carbon tetrachloride-induced hepatic fibrosis. Treatment with ebselen reduced steady-state levels of transforming growth factor-beta1, procollagen I and III, tissue inhibitor of metalloproteinase-1, cytochrome P4502E1 and placental form glutathione-S-transferase transcripts, and increased transcripts of matrix metalloproteinase-13.


CONCLUSIONS
These findings provide evidence that ebselen significantly causes the resolution of carbon tetrachloride-induced hepatic fibrosis in rats.
Wasser
S
S
Department of Pediatric Surgery, KK Women's and Children's Hospital, Singapore. shanthiwasser@pacific.net.sg
Lim
G Y
GY
Ong
C N
CN
Tan
C E
CE
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001393:Azoles / Q000494:pharmacology / Q000627:therapeutic use*; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects; D005982:Glutathione Transferase / Q000187:drug effects; D054833:Isoindoles; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008666:Metalloendopeptidases / Q000187:drug effects; D016566:Organoselenium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D011347:Procollagen / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012074:Remission Induction; D015291:Transforming Growth Factors / Q000187:drug effects
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D011347:Procollagen; C042986:ebselen; D015291:Transforming Growth Factors; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; D008666:Metalloendopeptidases