Formation and Persistence of Isoniazid-DNA Adducts in Mouse Tissues

Abstract

Further confirmation is provided to support the identity of the product formed by the in vitro eaction 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 INHytosine. Tissue differences in the persistence of these three DNA products suggest the presence of repair eactions for certain adducts. These processes and the effects of hepatotoxicity lead to a selective etention 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 pecies differences in its carcinogenicity are discussed.