Isoniazid-mediated irreversible inhibition of the myeloperoxidase antimicrobial system of the human neutrophil and the effect of thyronines.

ABSTRACT

During aerobic myeloperoxidase-catalysed oxidation of isoniazid at pH 7.8, compound III was generated. Oxidation of isoniazid or hydrazine sulphate at pH values of 6.5 or 7.8 in a myeloperoxidase-H2O2 system caused considerable haem loss, which was associated with compound III formation. Haem loss and also compound III formation could be inhibited when 8 microM thyroxine was included in the reaction mixtures. During the reaction with isoniazid, an intense pink-coloured pigment with maximum absorbance at 500 nm was formed which could be bleached with ascorbate or hypochlorous acid. The pigment was more stable at pH 7.8 than at pH 6.5. A similar pink colour was generated when a mixture of isoniazid and thyroxine in alkaline solution was irradiated with light of wavelength greater than 300 nm. A possible product of thyroxine oxidation, 3,5-diiodotyrosine, could not protect the enzyme against isoniazid-mediated haem loss and no colour formation was observed. Haem loss was most extensive when isoniazid was oxidised in a myeloperoxidase system at pH 7.8 in the presence of 0.1 M NaCl. Thyroxine (8 microM), however, could still inhibit haem loss under these conditions. A good correlation was found between haem loss and irreversible loss of peroxidase activity.