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'In vitro' interactions of monensin with hepatic xenobiotic metabolizing enzymes

L Ceppa1, M Dacasto, M Carletti

  • 1Dipartimento di Patologia Animale, settore di Farmacologia e Tossicologia, Univerisità di Torino, Italia.

Pharmacological Research
|February 7, 1998
PubMed

Insights

Monensin, an antibiotic, does not directly inhibit drug-metabolizing enzymes in vitro. However, it acts as a substrate for cytochrome P450 enzymes, indicating a role in drug metabolism.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Drug Metabolism

Background:

  • Monensin is a widely used antibiotic with anticoccidial and growth-promoting effects.
  • Its in vivo effects on drug-metabolizing enzymes vary with dosage and exposure duration.

Purpose of the Study:

  • To investigate the in vitro effects of monensin on drug-metabolizing enzymes in rat liver subfractions.
  • To determine if monensin acts as an inducer, inhibitor, or substrate of these enzymes.

Main Methods:

  • Incubation of monensin with hepatic microsomes and subfractions from untreated and phenobarbital-induced rats.
  • Assays for cytochrome P450 content, NADPH cytochrome c reductase, and glutathione S-transferase activity.
  • Measurement of NADPH oxidation rates and spectral analysis for P450 binding.
  • Determination of monensin O-demethylation rates and effects of inhibitors.

Main Results:

  • Monensin did not significantly alter cytochrome P450 content or the activity of NADPH cytochrome c reductase or glutathione S-transferase.
  • Monensin increased NADPH oxidation in microsomes and formed a type I binding spectrum with P450.
  • Monensin O-demethylation occurred in both untreated and induced microsomes, suggesting it is a substrate for P450 enzymes.
  • The O-demethylation reaction was dependent on NADPH and inhibited by metyrapone.

Conclusions:

  • Monensin is not a direct in vitro inhibitor of major drug-metabolizing enzymes.
  • Monensin is a substrate for P450-dependent monooxygenases, indicating its involvement in drug metabolism pathways.

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