Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children

Hironori Nagasaka, Tohru Yorifuji, Kunihiko Kobayashi, Hajime Takikawa, Haruki Komatsu, Ayano Inui, Tomoo Fujisawa, Takashi Miida, Hirokazu Tsukahara, Tomozumi Takatani, Hisamitsu Hayashi

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate.

Original languageEnglish
Pages (from-to)123-128
Number of pages6
JournalMolecular Genetics and Metabolism
Volume100
Issue number2
DOIs
Publication statusPublished - Jun 2010
Externally publishedYes

Fingerprint

Ornithine Carbamoyltransferase
Bile Acids and Salts
Liver
Pumps
Adenosine Triphosphate
Hyperammonemia
Transferases
phenylacetic acid
Bile Canaliculi
Cholestasis
Serum
Alanine Transaminase
Aspartic Acid
Intravenous Administration
Urea
Hepatocytes
Cultured Cells
Animals
Western Blotting
Cells

Keywords

  • 4-Phenylacetate
  • 4-Phenylbutyrate
  • Bile salt export pump
  • Cholestasis
  • Hyperammonemia
  • Ornithine transcarbamylase deficiency
  • Progressive intrahepatic cholestasis
  • Urea cycle defects

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children. / Nagasaka, Hironori; Yorifuji, Tohru; Kobayashi, Kunihiko; Takikawa, Hajime; Komatsu, Haruki; Inui, Ayano; Fujisawa, Tomoo; Miida, Takashi; Tsukahara, Hirokazu; Takatani, Tomozumi; Hayashi, Hisamitsu.

In: Molecular Genetics and Metabolism, Vol. 100, No. 2, 06.2010, p. 123-128.

Research output: Contribution to journalArticle

Nagasaka, Hironori ; Yorifuji, Tohru ; Kobayashi, Kunihiko ; Takikawa, Hajime ; Komatsu, Haruki ; Inui, Ayano ; Fujisawa, Tomoo ; Miida, Takashi ; Tsukahara, Hirokazu ; Takatani, Tomozumi ; Hayashi, Hisamitsu. / Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children. In: Molecular Genetics and Metabolism. 2010 ; Vol. 100, No. 2. pp. 123-128.
@article{7d430da74e3b488ca510edbd7d1bc0d5,
title = "Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children",
abstract = "4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate.",
keywords = "4-Phenylacetate, 4-Phenylbutyrate, Bile salt export pump, Cholestasis, Hyperammonemia, Ornithine transcarbamylase deficiency, Progressive intrahepatic cholestasis, Urea cycle defects",
author = "Hironori Nagasaka and Tohru Yorifuji and Kunihiko Kobayashi and Hajime Takikawa and Haruki Komatsu and Ayano Inui and Tomoo Fujisawa and Takashi Miida and Hirokazu Tsukahara and Tomozumi Takatani and Hisamitsu Hayashi",
year = "2010",
month = "6",
doi = "10.1016/j.ymgme.2010.02.008",
language = "English",
volume = "100",
pages = "123--128",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children

AU - Nagasaka, Hironori

AU - Yorifuji, Tohru

AU - Kobayashi, Kunihiko

AU - Takikawa, Hajime

AU - Komatsu, Haruki

AU - Inui, Ayano

AU - Fujisawa, Tomoo

AU - Miida, Takashi

AU - Tsukahara, Hirokazu

AU - Takatani, Tomozumi

AU - Hayashi, Hisamitsu

PY - 2010/6

Y1 - 2010/6

N2 - 4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate.

AB - 4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate.

KW - 4-Phenylacetate

KW - 4-Phenylbutyrate

KW - Bile salt export pump

KW - Cholestasis

KW - Hyperammonemia

KW - Ornithine transcarbamylase deficiency

KW - Progressive intrahepatic cholestasis

KW - Urea cycle defects

UR - http://www.scopus.com/inward/record.url?scp=77951975012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951975012&partnerID=8YFLogxK

U2 - 10.1016/j.ymgme.2010.02.008

DO - 10.1016/j.ymgme.2010.02.008

M3 - Article

C2 - 20219403

AN - SCOPUS:77951975012

VL - 100

SP - 123

EP - 128

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 2

ER -