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Bromobenzene and furosemide hepatotoxicity: alterations in glutathione, protein thiols, and calcium

K K Grewal1, E Rafeiro, W J Racz

  • 1Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, Canada.

Canadian Journal of Physiology and Pharmacology
|March 1, 1996
PubMed

Insights

This study investigated hepatotoxicity from bromobenzene and furosemide. Researchers found that calcium deregulation and thiol depletion do not initiate cell damage, challenging previous theories on drug-induced liver injury.

Area of Science:

  • Hepatotoxicity Research
  • Cellular Toxicology
  • Biochemical Mechanisms

Background:

  • The mechanisms underlying drug-induced hepatotoxicity, particularly from bromobenzene and furosemide, remain unclear.
  • Investigating the role of intracellular calcium homeostasis disturbances and thiol depletion in this process is crucial.

Purpose of the Study:

  • To examine if disruptions in intracellular calcium homeostasis, caused by reduced glutathione (GSH) and protein thiols (PSHs) depletion, initiate hepatotoxicity.
  • To determine the temporal relationship between calcium levels, thiol status, and cell damage in response to bromobenzene and furosemide.

Main Methods:

  • Isolated mouse hepatocytes were exposed to cytotoxic concentrations of bromobenzene or furosemide.
  • Cytosolic calcium concentration and thiol status (GSH and PSHs) were measured over time.
  • Plasma membrane integrity was assessed to determine the onset of cell damage.

Main Results:

  • Bromobenzene exposure led to significant GSH depletion, with plasma membrane damage preceding increases in cytosolic Ca2+ and PSH depletion.
  • Furosemide caused substantial GSH depletion, and cell damage occurred concurrently with Ca2+ increase and PSH depletion.
  • Cytosolic Ca2+ increases did not precede cytotoxicity, and PSH depletion did not correlate with the observed hepatotoxicity for either agent.

Conclusions:

  • The findings do not support a primary role for calcium deregulation in initiating bromobenzene or furosemide-induced hepatotoxicity.
  • Depletion of protein thiols (PSHs) is not directly correlated with the cytotoxic effects of these drugs.
  • Further research is needed to elucidate the exact events leading to reactive intermediate-induced hepatotoxicity.

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