Formation and persistence of isoniazid-DNA adducts in mouse tissues

Further confirmation is provided to support the identity of the product formed by the in vitro reaction of isoniazid (INH) with cytosine as 4-deamino-4-isoniazidocytosine (INH-cytosine). Use of INH-treated mice, in which the tissue DNA is prelabelled by the neonatal administration of [3H]-deoxycytidine, has revealed the presence of two other DNA products in addition to INH-cytosine. Tissue differences in the persistence of these three DNA products suggest the presence of repair reactions for certain adducts. These processes and the effects of hepatotoxicity lead to a selective retention of adducts in the DNA of lung which is the target tissue for INH-carcinogenicity in mice. INH-modified DNA templates are weakly promutagenic during in vitro DNA synthesis. The implications of these observations for the role of INH as an initiating agent and for the species differences in its carcinogenicity are discussed.