Hepatic glutathione and hepatotoxicity: changes induced by selected narcotics

Area of Science:

• Hepatology
• Pharmacology
• Toxicology

Background:

• Opioid agonists like propoxyphene and morphine can affect liver function.
• Previous studies suggest a link between opioid administration and liver injury.

Purpose of the Study:

• To investigate the effects of propoxyphene and morphine on hepatic glutathione levels and SGPT activity in male mice.
• To determine if naltrexone, a narcotic antagonist, can prevent these opioid-induced hepatic changes.
• To explore the relationship between glutathione depletion and opioid-induced hepatotoxicity.

Main Methods:

• Male mice were administered propoxyphene or morphine.
• Hepatic glutathione levels and serum glutamic-pyruvic transaminase (SGPT) activity were measured at various time points.
• Naltrexone was administered as a pretreatment to assess its antagonistic effects.
• The effects of other narcotic agonists (L-alpha-acetylmethadol, norLAAM, SKF525-A) were also evaluated with naltrexone pretreatment.

Main Results:

• Propoxyphene and morphine significantly lowered hepatic glutathione and increased SGPT activity, with maximal effects observed 3-6 hours post-administration.
• Naltrexone abolished the glutathione depletion caused by propoxyphene and morphine but did not affect propoxyphene-induced SGPT elevations.
• Naltrexone antagonized glutathione depletion and SGPT elevations induced by L-alpha-acetylmethadol and norLAAM, but only partially lessened changes induced by SKF525-A.
• Morphine-induced hepatic changes potentiated acetaminophen and cocaine-induced hepatotoxicity.

Conclusions:

• Narcotic agonists morphine, L-alpha-acetylmethadol, norLAAM, and propoxyphene reduce hepatic glutathione and cause hepatocellular damage.
• The depletion of hepatic glutathione and the induction of hepatocellular damage by these narcotic agonists appear to be independent effects.