Inhibition of liver methionine adenosyltransferase gene expression by 3-methylcolanthrene: protective effect of S-adenosylmethionine

Methionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the synthesis of S-adenosylmethionine (AdoMet), the most important biologic al methyl donor. Liver MAT I/III is the product of the MAT1A gene. Hepatic MAT I/III activity and MAT1A expression are compromised under pathological conditions such as alcoholic liver disease and hepatic cirrhosis, and this gene is silenced upon neoplastic transformation of the liver. Ln the presen t work, we evaluated whether MAT1A expression could be targeted by the poly cyclic arylhydrocarbon (PAH) 3-methylcholanthrene (3-MC) in rat liver and c ultured hepatocytes. MAT1A mRNA levels were reduced by 50% following in viv o administration of 3-MG to adult male rats (100 mg/kg, p.o., 4 days' treat ment). This effect was reproduced in a time- and dose-dependent fashion in cultured rat hepatocytes, and was accompanied by the induction of cytochrom e P450 1Al gene expression. This action of 3-MG was mimicked by other PAHs such as benzo[a] pyrene and benzo[e]pyrene. but not by the model arylhydroc arbon receptor (AhR) activator 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3-MG in hibited transcription driven by a MAT1A promoter-reporter construct transfe cted into rat hepatocytes, but MAT1A mRNA stability was not affected. We re cently showed that liver MAT1A expression is induced by AdoMet in cultured hepatocytes. Here, we observed that exogenously added AdoMet prevented the negative effects of 3-MG on MAT1A expression. Taken together, our data demo nstrate that liver MAT1A gene expression is targeted by PAHs, independently of AhR activation. The effect of AdoMet may be part of the protective acti on of this molecule in Liver damage. (C) 2001 Elsevier Science Inc. All rig hts reserved.