Isoniazid-induced hepatotoxicity and the metabolite hydrazine —Some of the active metabolic intermediates resulted from hydrazine—

Abstract

It is important to introduce our studies about isoniazid (INH) —induced hepatitis, since INH is widely used as a first line drug for the treatment of tuberculosis all over the world. From a lot of experimental data obtained by us it is clarified that hydrazine (Hz), one of INH metabolites, is a main toxigen of INH-induced hepatitis, and its effective toxins are Hz radical (N H-NH₂) and/or diimide (HN=NH) rather than acetylhydrazine. The radical formed during oxidative metabolism of Hz in rat liver microsomes was spintrapped with α-phenyl-tert-butylnitrone. The trapped species was identified as Hz radical by the examination of its ESR and mass spectra. Further enzymatic experiments provided the evidence, i. e. Hz radical was formed through hydrogen abstraction from Hz by superoxide anion which was released by reduced NADPH cytochrome P-450 (fp₂H₂)-mediated one-electron donation to oxygen molecules. Although rifampicin(RMP)is well-known as an inducer of cytochrome P-450, it was demonstrated by us that the treatment of rats with RMP activated not only INH-amidase but also fp₂ in the liver microsomes of Hz-administered rats. These observations strongly suggest that INHRMP coadministration can accelerate Hz formation from INH initially, following a hydrogen abstraction of Hz to its radical by superoxide anion, and further oxidation of the radical to diimide is increased by cytochrome P-450. These processes might be a key factor of INH-induced hepatitis enhanced by RMP in tuberculous patients on INH-RMP treatment.