Oxygen activation during drug metabolism

Area of Science:

• Biochemistry
• Pharmacology
• Toxicology

Background:

• Drug metabolism often involves cytochrome P-450 catalyzed two-electron oxidation.
• However, one-electron oxidation pathways leading to radical formation are increasingly recognized.
• The role of peroxidase-hydrogen peroxide systems in drug oxidation requires further elucidation.

Purpose of the Study:

• To investigate the mechanism of peroxidase-H2O2 catalyzed drug oxidation.
• To identify drugs that undergo redox cycling and radical formation.
• To explore the implications for cellular processes like oxygen uptake and glutathione oxidation.

Main Methods:

• Peroxidase-catalyzed oxidation of various drugs in the presence of glutathione (GSH), NADH, or arachidonate.
• Measurement of oxygen uptake, radical formation (thiyl, superoxide), and glutathione disulfide (GSSG) production.
• Comparison of drug responses and correlation with known metabolic pathways.

Main Results:

• Catalytic amounts of specific drugs (morphine, phenothiazines, acetaminophen, etc.) induced extensive oxidation of GSH to GSSG and significant oxygen uptake.
• A redox cycling mechanism was proposed, generating superoxide radicals and hydrogen peroxide.
• Other drugs (dopamine, methyl-alpha-dopa) did not induce oxygen uptake but led to GSH depletion via conjugate formation.

Conclusions:

• Peroxidase-H2O2 systems can catalyze one-electron oxidation of certain drugs, leading to radical formation and reactive oxygen species.
• This pathway contributes to drug-induced oxidative stress and differs from typical cytochrome P-450 two-electron oxidation.
• Findings highlight the importance of considering one-electron oxidation mechanisms in drug metabolism and toxicity.