Nafenopin-induced rat liver peroxisome proliferation reduces DNA methylation by N-nitrosodimethylamine in vivo.
The hypolipidaemic drug nafenopin (NAF) has been shown to enhance the hepatocarcinogenic effect of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine in rats. We have investigated whether the NAF-induced peroxisome proliferation in hepatocytes interferes with NDMA's metabolism and interaction with DNA. Adult male Wistar rats received a single i.p. injection of [14C]NDMA (2 mg/kg) and were killed 4 h later. DNA was isolated from liver and kidney, hydrolysed in 0.1 N HCl and analysed by Sephasorb chromatography. In rats pre-treated with NAF (0.2% in the diet over a period of 3 weeks), the concentration of N7-methylguanine in hepatic DNA (mumol/mol guanine) was 46% below control values. This is probably due to the greater amount of target DNA, as NAF caused a marked hepatomegaly with a 50% increase in total liver DNA content. Concentrations of N7-methylguanine in kidney DNA were twice as high in NAF-pre-treated animals when compared to control rats. This is unlikely to result from a shift in the metabolism of NDMA from liver to other rat tissues since the time course and extent of the conversion of [14C]NDMA to 14CO2 and 14C-labelled urinary metabolites were identical in NAF-treated and control animals. There was no indication that NAF inhibits the activity of the hepatic O6-alkylguanine-DNA alkyltransferase.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D008745:Methylation; D008830:Microbodies / Q000187:drug effects*; D009255:Nafenopin / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D011422:Propionates; D009255:Nafenopin; D004247:DNA; D004128:Dimethylnitrosamine