Inhibition of leukotriene ω‐oxidation by isonicotinic acid hydrazide (isoniazid)

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Abstract
Metabolism of leukotrienes via .omega.-oxidation represents a major degradative and inactivating pathway of these biologically active icosanoids. Isonicotinic acid hydrazide (isoniazid) inhibited this process in rats in vivo, in the isolated perfused rat liver, and hepatic microsomes. The in vivo catabolism of leukotriene Er via N-acetyl-leukotriene E4 to its .omega.-oxidized metabolites was inhibited by 50% or 71% using single intravenous isoniazid doses of 0.6 mmol or 1.0 mmol/kg body mass, respectively. Isoniazid interfered with leukotriene catabolism at the initial .omega.-oxidation step, resulting in an accumulation of N-acetyl-leukotriene E4. Analogous although weaker inhibition of leukotriene .omega.-oxidation in vivo was observed by pretreatment with isonicotinic acid 2-isopropylhydrazide and monoacetyl hydrazine. In the isolated perfused liver, isoniazid at concentrations varying over 0.2-10 mM decreased the .omega.-oxidation of cysteinyl leukotrienes dose-dependently by up to 94%. .omega.-Oxidation of both leukotriene E4 and leukotriene B4 by rat liver microsomes was inhibited by isoniazid, isonicotinic acid 2-isopropylhydrazide, and monoacetyl hydrazine with half-maximal concentrations in the range of 5-15 mM. Our measurements indicate that the impairment of leukotriene .omega.-oxidation by isoniazid involves both cytochrome-P450-dependent enzyme systems responsible for .omega.-oxidation of leukotriene E4 and leukotriene B4. In effect, under isoniazid treatment one can expect a prolongation of the proinflammatory actions of endogenously produced leukotrienes.

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