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Liver injury by the false morel poison gyromitrin
Abstract:
After oral application of the mushroom poison gyromitrin a time and dose dependent decrease of cytochrome P-450 was found in rat liver microsomes. The maximal decrease to about 50-60% of the control (after 200 mg/kg, 80% of LD50) was observed 8-12h after application, a normalization after 48 h. The inhibition of cytochrome P-450 mediated metabolism of aminopyrine and p-nitroanisole corresponds to the decrease of cytochrome P-450. The specific activity of cytochrome P-450 remains unchanged while that of cytochrome P-448 is decreased as shown by means of the metabolism of ethoxycoumarin or ethoxyresorufin. Comparable results were obtained after application of N-methyl-N-formylhydrazine (MFH) which is formed from gyromitrin rapidly by hydrolysis. An attack on the endoplasmatic membrane with a stimulation of lipid peroxidation is discussed.
Insights
Gyromitrin, a mushroom poison, significantly reduces cytochrome P-450 levels in rat liver microsomes. This effect is dose-dependent and reversible, impacting drug metabolism.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Cytochrome P-450 enzymes are crucial for metabolizing xenobiotics.
- Gyromitrin is a toxic compound found in certain mushrooms.
- Understanding gyromitrin's effects on liver enzymes is important for toxicology.
Purpose of the Study:
- To investigate the impact of gyromitrin on cytochrome P-450 levels and activity in rat liver microsomes.
- To determine the time course and dose-dependency of gyromitrin's effects.
- To explore the mechanism underlying gyromitrin-induced liver toxicity.
Main Methods:
- Oral administration of gyromitrin to rats at varying doses.
- Measurement of cytochrome P-450 content in liver microsomes.
- Assay of specific enzyme activities using substrates like aminopyrine, p-nitroanisole, ethoxycoumarin, and ethoxyresorufin.
- Analysis of N-methyl-N-formylhydrazine (MFH) effects.
Main Results:
- Gyromitrin caused a time- and dose-dependent decrease in cytochrome P-450, reaching 50-60% of control levels.
- Maximal reduction occurred 8-12 hours post-administration, with normalization by 48 hours.
- Metabolism of aminopyrine and p-nitroanisole was inhibited, correlating with cytochrome P-450 decrease.
- Specific activity of cytochrome P-450 remained unchanged, but cytochrome P-448 activity decreased.
- Similar effects were observed with N-methyl-N-formylhydrazine (MFH).
Conclusions:
- Gyromitrin and its metabolite MFH are potent inhibitors of cytochrome P-450 in rat liver.
- The observed effects suggest potential damage to the endoplasmic reticulum and stimulation of lipid peroxidation.
- These findings highlight the hepatotoxic potential of gyromitrin through its impact on drug-metabolizing enzymes.