Inhibitory effect of tetrahydroswertianolin on tumor necrosis factor-α-dependent hepatic apoptosis in mice

Kouji Hase, Quanbo Xiong, Purusotam Basnet, Tsuneo Namba, Shigetoshi Kadota

Research output: Contribution to journalArticle

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Abstract

We investigated the effect of tetrahydroswertianolin (THS), a hepatoprotective agent from Swertia japonica, on tumor necrosis factor-α (TNF-α)-dependent hepatic apoptosis induced by D-galactosamine (D-GalN) (700 mg/kg, i.p.) and lipopolysaccharide (LPS) (10 μg/kg, i.p.) in mice. Apoptotic symptoms were observed at the initial stage of liver damage. By 5 hr after intoxication, hepatic DNA fragmentation had risen to 2123%, with the value in untreated mice set at 100%, without a significant elevation of serum alanine transaminase (ALT) activity. There was a parallel increase in hepatocytes undergoing chromatin condensation and apoptotic body formation. By 8 hr after intoxication, serum ALT activity had risen to 3707 U/L. Pretreatment with THS (50 mg/kg, p.o.) at 18 and 2 hr before intoxication significantly reduced DNA fragmentation to 821% of that in untreated mice and prevented the emergence of chromatin condensation and apoptotic body formation. A significant and dose-dependent reduction in serum ALT activity at 8 hr also was observed with THS pretreatment. These effects of THS were different from those observed from pretreatment with glycyrrhizin (GCR), which is a clinically used hepatoprotective agent with membrane-stabilizing activity. GCR pretreatment (100 mg/kg, p.o.) did not inhibit hepatic DNA fragmentation (1588% of untreated mice), although this compound significantly protected against serum ALT elevation (1463 U/L). These data suggest that an inhibitory effect on the progression of hepatic apoptosis prior to liver injury may be involved in the hepatoprotective mechanisms of THS, whereas it appears that GCR affects the processes after apoptosis. In a separate experiment, we found that the concentration of serum TNF-α rose to 2016 pg/mL at 1 hr after intoxication of mice with D-GalN and LPS, but this increase was suppressed by THS pretreatment (10, 50, or 200 mg/kg, p.o.) to 716, 454, or 406 pg/mL, respectively. Further study with a reverse transcriptase-polymerase chain reaction method showed that THS blocked TNF-α production at the transcriptional level. Because TNF-α is a critical mediator to elicit apoptosis in this model, the property of suppressing TNF-α production may be of prime importance for THS inhibition of hepatic apoptosis. Copyright (C) 1999 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)1431-1437
Number of pages7
JournalBiochemical Pharmacology
Volume57
Issue number12
DOIs
Publication statusPublished - 1999 Jun 15
Externally publishedYes

Fingerprint

Tumor Necrosis Factor-alpha
Apoptosis
Liver
Glycyrrhizic Acid
Alanine Transaminase
DNA Fragmentation
Serum
Galactosamine
Chromatin
Lipopolysaccharides
Condensation
DNA
Swertia
tetrahydroswertianolin
Polymerase chain reaction
RNA-Directed DNA Polymerase
Reverse Transcriptase Polymerase Chain Reaction
Hepatocytes
Membranes
Wounds and Injuries

Keywords

  • Apoptosis
  • D-galactosamine
  • DNA fragmentation
  • Lipopolysaccharide
  • Tetrahydroswertianolin
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibitory effect of tetrahydroswertianolin on tumor necrosis factor-α-dependent hepatic apoptosis in mice. / Hase, Kouji; Xiong, Quanbo; Basnet, Purusotam; Namba, Tsuneo; Kadota, Shigetoshi.

In: Biochemical Pharmacology, Vol. 57, No. 12, 15.06.1999, p. 1431-1437.

Research output: Contribution to journalArticle

Hase, Kouji ; Xiong, Quanbo ; Basnet, Purusotam ; Namba, Tsuneo ; Kadota, Shigetoshi. / Inhibitory effect of tetrahydroswertianolin on tumor necrosis factor-α-dependent hepatic apoptosis in mice. In: Biochemical Pharmacology. 1999 ; Vol. 57, No. 12. pp. 1431-1437.
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