Induction of rat liver O6-alkylguanine-DNA alkyltransferase by bleomycin.

Alkyl adducts at the O6-position of guanine constitute promutagenic DNA lesions likely to be involved in the initiation of malignant transformation. They can be removed by a cellular acceptor protein termed O6-alkylguanine-DNA alkyltransferase (AT). In rat liver this repair enzyme can be induced by a variety of hepatotoxins, partial hepatectomy and X-irradiation. This paper describes a stimulation of the hepatic AT by treatment of rats with the radiomimetic agent, bleomycin. Induction of AT is dose-dependent up to 20 mg bleomycin/kg and appears to level off with higher doses. Enhancement of O6-meG repair is detectable within 24 h after a single i.p. injection. Maximum AT induction was reached after 6 days and amounted to 350% of the control levels. The enhancement of AT activity is not associated with acute liver injury and initially coincides with an inhibition of [3H]deoxythymidine incorporation into hepatic DNA. This indicates that AT induction in rat liver is not necessarily dependent on tissue necrosis with increased cell replication. Since bleomycin does not produce DNA lesions recognized and repaired by the AT, the hypothesis is entertained that AT induction by these agents is part of a concerted reaction to radiation-type DNA damage.