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Myeloperoxidase-mediated activation of xenobiotics by human leukocytes
1Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Abstract:
Peripheral blood leukocytes contain a variety of enzymes that are capable of metabolising xenobiotics. The enzyme myeloperoxidase (MPO) appears to be the most important for drug metabolism. MPO is a peroxidase/oxidase and generates the powerful oxidant hypochlorous acid. MPO- or MPO-generated oxidants are capable of oxidizing a wide variety of compounds and a broad range of functional groups, especially those that contain nitrogen and sulfur. Leukocytes have a role in immune response; therefore, reactive intermediates generated by leukocyte metabolism of xenobiotics may have a role in idiosyncratic drug reactions, particularly those that are immune-mediated such as drug-induced lupus or agranulocytosis.
Insights
Peripheral blood leukocytes metabolize drugs using enzymes, notably myeloperoxidase (MPO). MPO-generated oxidants can alter drug compounds, potentially contributing to immune-mediated idiosyncratic drug reactions.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Peripheral blood leukocytes possess enzymes crucial for xenobiotic metabolism.
- Myeloperoxidase (MPO) is identified as a key enzyme in this metabolic process.
- MPO generates hypochlorous acid, a potent oxidant.
Purpose of the Study:
- To investigate the role of leukocyte enzymes, particularly MPO, in xenobiotic metabolism.
- To explore the potential involvement of MPO-generated reactive intermediates in drug reactions.
Main Methods:
- Analysis of enzyme activities in peripheral blood leukocytes.
- Characterization of MPO's oxidative capabilities on various compounds.
- Correlation of xenobiotic metabolism by leukocytes with immune-mediated drug reactions.
Main Results:
- Leukocytes contain multiple xenobiotic-metabolizing enzymes, with MPO being prominent.
- MPO effectively oxidizes diverse compounds, especially those with nitrogen and sulfur functional groups.
- Reactive intermediates from leukocyte xenobiotic metabolism may link to idiosyncratic drug reactions.
Conclusions:
- Myeloperoxidase plays a significant role in the metabolism of xenobiotics by leukocytes.
- The oxidative activity of MPO and its generated intermediates are implicated in immune-mediated adverse drug events.
- Understanding leukocyte xenobiotic metabolism is vital for predicting and managing idiosyncratic drug reactions like drug-induced lupus.