Metabolism of isoniazid by activated leukocytes. Possible role in drug-induced lupus.
The tuberculostatic agent isoniazid has been implicated in inducing various idiosyncratic reactions including drug-induced lupus. The mechanism is unknown but may involve a reactive metabolite of the drug. Isoniazid was oxidized by activated leukocytes to isonicotinic acid. Myeloperoxidase is likely the enzyme in the leukocyte involved, since the oxidation was inhibited by azide, which inhibits myeloperoxidase, and by catalase, which catalyzes the breakdown of hydrogen peroxide. The same metabolic profile was observed when isoniazid was incubated with purified myeloperoxidase and hydrogen peroxide. The rate of the reaction was increased in the presence of chloride. Hypochlorous acid was also able to oxidize isoniazid to isonicotinic acid. Isoniazid, or an oxidative product, inhibited the reaction when high initial substrate concentrations were used. Isoniazid is oxidized by activated leukocytes, possibly to a reactive intermediate, which may have implications for isoniazid-induced lupus.
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
A H
AH
Hofstra
S M
SM
Li-Muller
J P
JP
Uetrecht
D006801:Humans; D007538:Isoniazid / Q000009:adverse effects / Q000378:metabolism*; D007539:Isonicotinic Acids / Q000138:chemical synthesis; D007962:Leukocytes / Q000378:metabolism*; D008177:Lupus Vulgaris / Q000139:chemically induced*; D009195:Peroxidase / Q000378:metabolism
D007539:Isonicotinic Acids; D009195:Peroxidase; D007538:Isoniazid