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Effect of alpha-methyldopa on pentoxyresorufin O-dealkylation in liver microsomes from rats treated with

Z Veres1, T Szakács, L Vereczkey

  • 1Department of Biochemical Pharmacology, Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1525 Budapest, Hungary. veres@chemres.hu

Archives of Biochemistry and Biophysics
|July 27, 2001
PubMed

Insights

Pentoxyresorufin O-dealkylation (PROD) activity loss, linked to lipid peroxidation, was prevented by alpha-methyldopa (AMD). AMD

Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • Cytochrome P450 (CYP) enzymes are crucial for drug metabolism.
  • Enzyme activity can be compromised by oxidative stress and lipid peroxidation.
  • Pentoxyresorufin O-dealkylation (PROD) is a key CYP-dependent metabolic pathway.

Purpose of the Study:

  • To investigate the protective mechanisms of alpha-methyldopa (AMD) against enzyme inactivation.
  • To elucidate the role of lipid peroxidation in CYP enzyme activity loss.
  • To understand how AMD modulates oxidative stress during enzyme assays.

Main Methods:

  • In vitro microsomal assays using rat liver microsomes.
  • Measurement of PROD activity.
  • Quantification of thiobarbituric acid reactive substances (TBARS) as a marker of lipid peroxidation.
  • Preincubation studies with NADPH and varying concentrations of AMD, ascorbate, and glutathione (GSH).

Main Results:

  • Preincubation with NADPH led to a significant loss of PROD activity.
  • This activity loss correlated with increased TBARS formation, indicating lipid peroxidation.
  • Alpha-methyldopa (AMD) at 50 microM completely protected PROD activity and reduced lipid peroxidation.
  • The combination of AMD with ascorbate or GSH diminished AMD's protective effect.

Conclusions:

  • AMD protects CYP-dependent PROD activity from NADPH-induced inactivation.
  • The protective effect of AMD is likely mediated by scavenging reactive oxygen species.
  • Ferric ion chelation may also contribute to AMD's ability to preserve enzyme function.
  • These findings highlight AMD's potential role in mitigating drug-induced oxidative stress in metabolic pathways.

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