Temporal cell-type-specific mRNA expression of O6-methylguanine-DNA methyltransferases in liver of rats treated with dimethylnitrosamine

Abstract

The intercellular distribution of O6-methylguanine-DNA methyltransferase (MGMT) mRNA expression has been investigated at the individual cell level in the liver of rats treated with dimethylnitrosamine using in situ hybridization. Male BDIV rats were orally administered with a single dose of dimethylnitrosamine (5 or 10 mg/kg) and were killed at 24, 48, and 96 hours after exposure. Constitutive MGMT mRNA expression was found in bile duct cells, vascular endothelial cells, and fibrous cells; however, weak or negative expression was detected in hepatocytes and Kupffer cells. On the other hand, after exposure to dimethylnitrosamine, inducible MGMT mRNA was rapidly expressed in hepatocytes, especially in the centrilobular area at earlier time points, confirming our previous studies in which enzymatic activity has been measured in different purified cell populations obtained by differential centrifugation. Immunohistochemical detection of the O6-methylguanine-DNA adduct formation was demonstrated in a dose-dependent fashion and was mainly found in the centrilobular hepatocytes where high levels of MGMT mRNA were present. These results suggest a correlation between the induction of this repair activity and DNA damage; however, the relationship between MGMT mRNA and enzyme activity remains to be fully established for all cell types.