The role of oxygen free radicals in isoniazid-induced hepatotoxicity

Isoniazid and its metabolites acetylisoniazid, hydrazine and monoacetylhydr azine were investigated for generation of oxygen free radicals during incub ation with rat liver slices. Lipid peroxidation was assessed by the thiobar bituric acid reactive substances test using malonaldehyde as the external s tandard, while hepatotoxicity was assessed by histopathology studies. Malon aldehyde formed in liver slices after 10 hours of incubation with the drugs was 1.28 +/- 0.24 nmol/mg for isoniazid (control 1.12 +/- 0.17 nmol/mg); 0 .88 +/- 0.45 nmol/mg for acetylisoniazid (control 0.84 +/- 0.42 nmol/mg); 1 .43 +/- 0.14 nmol/mg for monoacetylhydrazine (control 1.10 +/- 0.12 nmol/mg ) and 1.36 +/- 0.02 nmol/mg for hydrazine (control 1.13 +/- 0.04 nmol/mg). Histologically, all slices exhibited hepatic necrosis by 4 hours. However, hydrazine-induced hepatotoxicity was characterized by nuclear hyperchromats ia, karyolysis and karyohexis while monoacetylhydrazine exhibited hydropic karyomegaly only. Isoniazid and acetylisoniazid cytotoxicity exhibited a mi xture of the above features such that it could be attributed to the two met abolites, hydrazine and monoacetylhydrazine. In conclusion, ther was no evi dence implicating oxygen free radicals in isoniazid-induced hepatotoxicity; however, the histopathology findings indicate a need for a review of our k nowledge on pathognomonic features of isoniazid hepatotoxicity. (C) 1998 Pr ous Science. All rights reserved.