Phenylbutyrate exerts adverse effects on liver regeneration and amino acid concentrations in partially hepatectomized rats

Abstract

Phenylbutyrate is recommended in urea cycle disorders and liver injury to enhance nitrogen disposal by the urine. However, hypothetically there may be adverse responses to the use of phenylbutyrate in the treatment of liver disease because of its role as a histone deacetylase inhibitor and its stimulatory effect on branched-chain alpha-keto acid dehydrogenase, the rate-limiting enzyme in the catabolism of branched-chain amino acids (BCAA; valine, leucine and isoleucine). We report the effects of phenylbutyrate on liver regeneration and amino acid levels in plasma of partially hepatectomized (PH) rats. Phenylbutyrate or saline was administered at 12-h intervals to PH or laparotomized rats. Phenylbutyrate delayed the onset of liver regeneration compared to the saline-treated controls, as indicated by lower hepatic DNA specific activities 18 and 24() h post-PH, decreased hepatic fractional protein synthesis rates 24h post-PH and lowered the increases in liver weights and hepatic protein and DNA contents 48h after PH. Hepatic DNA fragmentation (a hallmark of apoptosis) was higher in the phenylbutyrate-treated animals than in controls. Phenylbutyrate decreased the glutamine and BCAA concentrations and the ratio of the BCAA to aromatic amino acids (phenylalanine and tyrosine) in the blood plasma in both hepatectomized and laparotomized animals. In conclusion, the delayed onset of liver regeneration and the decrease in BCAA/AAA ratio in blood suggest that phenylbutyrate administration may be disastrous in subjects with acute hepatic injury and BCAA supplementation is needed when phenylbutyrate is used therapeutically.