S-Adenosylmethionine but not glutathione protects against galactosamine-induced cytotoxicity in rat hepatocyte cultures

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A gradual but extensive depletion of hepatic GSH has long been known to accompany development of galactosamine-induced hepatotoxicity in rats, and some protection from liver injury has been observed after administration of sulfhydryl-donating compounds. Although these observations support a key role for GSH in the underlying mechanism, the impact of GSH depletion and repletion on the hepatotoxic response to galactosamine is unclear. To investigate the role of GSH in galactosamine-induced liver injury, we examined the effect of modulating GSH content on galactosamine toxicity in rat primary hepatocyte cultures. Galactosamine (4 mM) cytotoxicity was assessed by release of lactate dehydrogenase into the culture medium, and hepatocellular GSH content was measured by HPLC with electrochemical detection. The data indicated that prior depletion of GSH with either diethyl maleate or buthionine sulfoximine significantly enhanced galactosamine toxicity; however, addition of GSH-ester or alternate sulfur nucleophiles at various times during the incubation did not abrogate toxicity. In contrast, co-addition of S-adenosylmethionine (SAMe) with galactosamine exerted a marked protective effect without significantly altering hepatocyte GSH content. These data suggest that GSH depletion is not directly involved in the sequelae for galactosamine-induced hepatotoxicity, and raise the possibility that SAMe may have hepatoprotective effects that are not dependent on its ability to enhance GSH synthesis.

Original languageEnglish (US)
Pages (from-to)175-184
Number of pages10
JournalToxicology
Volume222
Issue number3
DOIs
StatePublished - May 15 2006

Fingerprint

S-Adenosylmethionine
Galactosamine
Cytotoxicity
Cell culture
Glutathione
Rats
Hepatocytes
Toxicity
diethyl maleate
Liver
Buthionine Sulfoximine
Nucleophiles
Wounds and Injuries
L-Lactate Dehydrogenase
Sulfur
Sulfhydryl Compounds
Culture Media
Esters
High Pressure Liquid Chromatography

Keywords

  • Cysteamine
  • Galactosamine
  • Glutathione
  • Glutathione ethyl-ester
  • Hepatocyte cultures
  • Hepatocytes
  • Hepatotoxicity
  • N-acetylcysteine
  • S-adenosylmenthionine

ASJC Scopus subject areas

  • Toxicology

Cite this

@article{8e820538c7bb430fa33122d858d4793c,
title = "S-Adenosylmethionine but not glutathione protects against galactosamine-induced cytotoxicity in rat hepatocyte cultures",
abstract = "A gradual but extensive depletion of hepatic GSH has long been known to accompany development of galactosamine-induced hepatotoxicity in rats, and some protection from liver injury has been observed after administration of sulfhydryl-donating compounds. Although these observations support a key role for GSH in the underlying mechanism, the impact of GSH depletion and repletion on the hepatotoxic response to galactosamine is unclear. To investigate the role of GSH in galactosamine-induced liver injury, we examined the effect of modulating GSH content on galactosamine toxicity in rat primary hepatocyte cultures. Galactosamine (4 mM) cytotoxicity was assessed by release of lactate dehydrogenase into the culture medium, and hepatocellular GSH content was measured by HPLC with electrochemical detection. The data indicated that prior depletion of GSH with either diethyl maleate or buthionine sulfoximine significantly enhanced galactosamine toxicity; however, addition of GSH-ester or alternate sulfur nucleophiles at various times during the incubation did not abrogate toxicity. In contrast, co-addition of S-adenosylmethionine (SAMe) with galactosamine exerted a marked protective effect without significantly altering hepatocyte GSH content. These data suggest that GSH depletion is not directly involved in the sequelae for galactosamine-induced hepatotoxicity, and raise the possibility that SAMe may have hepatoprotective effects that are not dependent on its ability to enhance GSH synthesis.",
keywords = "Cysteamine, Galactosamine, Glutathione, Glutathione ethyl-ester, Hepatocyte cultures, Hepatocytes, Hepatotoxicity, N-acetylcysteine, S-adenosylmenthionine",
author = "McMillan, {Jo Ellyn M.} and McMillan, {David C.}",
year = "2006",
month = "5",
day = "15",
doi = "10.1016/j.tox.2006.02.013",
language = "English (US)",
volume = "222",
pages = "175--184",
journal = "Toxicology",
issn = "0300-483X",
publisher = "Elsevier Ireland Ltd",
number = "3",

}

TY - JOUR

T1 - S-Adenosylmethionine but not glutathione protects against galactosamine-induced cytotoxicity in rat hepatocyte cultures

AU - McMillan, Jo Ellyn M.

AU - McMillan, David C.

PY - 2006/5/15

Y1 - 2006/5/15

N2 - A gradual but extensive depletion of hepatic GSH has long been known to accompany development of galactosamine-induced hepatotoxicity in rats, and some protection from liver injury has been observed after administration of sulfhydryl-donating compounds. Although these observations support a key role for GSH in the underlying mechanism, the impact of GSH depletion and repletion on the hepatotoxic response to galactosamine is unclear. To investigate the role of GSH in galactosamine-induced liver injury, we examined the effect of modulating GSH content on galactosamine toxicity in rat primary hepatocyte cultures. Galactosamine (4 mM) cytotoxicity was assessed by release of lactate dehydrogenase into the culture medium, and hepatocellular GSH content was measured by HPLC with electrochemical detection. The data indicated that prior depletion of GSH with either diethyl maleate or buthionine sulfoximine significantly enhanced galactosamine toxicity; however, addition of GSH-ester or alternate sulfur nucleophiles at various times during the incubation did not abrogate toxicity. In contrast, co-addition of S-adenosylmethionine (SAMe) with galactosamine exerted a marked protective effect without significantly altering hepatocyte GSH content. These data suggest that GSH depletion is not directly involved in the sequelae for galactosamine-induced hepatotoxicity, and raise the possibility that SAMe may have hepatoprotective effects that are not dependent on its ability to enhance GSH synthesis.

AB - A gradual but extensive depletion of hepatic GSH has long been known to accompany development of galactosamine-induced hepatotoxicity in rats, and some protection from liver injury has been observed after administration of sulfhydryl-donating compounds. Although these observations support a key role for GSH in the underlying mechanism, the impact of GSH depletion and repletion on the hepatotoxic response to galactosamine is unclear. To investigate the role of GSH in galactosamine-induced liver injury, we examined the effect of modulating GSH content on galactosamine toxicity in rat primary hepatocyte cultures. Galactosamine (4 mM) cytotoxicity was assessed by release of lactate dehydrogenase into the culture medium, and hepatocellular GSH content was measured by HPLC with electrochemical detection. The data indicated that prior depletion of GSH with either diethyl maleate or buthionine sulfoximine significantly enhanced galactosamine toxicity; however, addition of GSH-ester or alternate sulfur nucleophiles at various times during the incubation did not abrogate toxicity. In contrast, co-addition of S-adenosylmethionine (SAMe) with galactosamine exerted a marked protective effect without significantly altering hepatocyte GSH content. These data suggest that GSH depletion is not directly involved in the sequelae for galactosamine-induced hepatotoxicity, and raise the possibility that SAMe may have hepatoprotective effects that are not dependent on its ability to enhance GSH synthesis.

KW - Cysteamine

KW - Galactosamine

KW - Glutathione

KW - Glutathione ethyl-ester

KW - Hepatocyte cultures

KW - Hepatocytes

KW - Hepatotoxicity

KW - N-acetylcysteine

KW - S-adenosylmenthionine

UR - http://www.scopus.com/inward/record.url?scp=33646110771&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646110771&partnerID=8YFLogxK

U2 - 10.1016/j.tox.2006.02.013

DO - 10.1016/j.tox.2006.02.013

M3 - Article

C2 - 16564122

AN - SCOPUS:33646110771

VL - 222

SP - 175

EP - 184

JO - Toxicology

JF - Toxicology

SN - 0300-483X

IS - 3

ER -