Related Experiment Videos
Organ specificity, metabolism and reaction with DNA of aliphatic nitrosomethylalkylamines
P Kleihues1, E von Hofe, I Schmerold
1Department of Pathology, University of Zürich, Switzerland.
Abstract:
Aliphatic nitrosomethylalkylamines are carcinogens with a remarkable organ specificity in rats, the principal targets being liver, oesophagus and bladder. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6-h survival) of each of 12 homologues, ranging from N-nitrosodimethylamine (NDMA, C1) to N-nitrosomethyldodecylamine (C12). Methylpurines (7- and O6-methylguanine; 7-meGua and O6-meGua) were determined by cation-exchange high-performance liquid chromatography with fluorescence detection. Highest levels of hepatic DNA methylation were found with NDMA (C1) and N-nitrosoethylmethylamine (NEMA, C2), the most potent hepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length from C1 to C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenicity, the most effective agents being the butyl and pentyl derivatives (C4 and C5). Levels of DNA methylation in bladder epithelium were close to the limit of detection (C6,C9,C10,C12) and there was no apparent correlation with carcinogenicity. It is concluded that initiation of malignant transformation by DNA methylation alone (through hydroxylation of the nitrosamine at the methylene alpha-carbon) could be operative for C1-C5. For the higher homologues, this type of DNA modification is insufficient to explain the complex pattern of tissue specificity.
Insights
DNA methylation in rat tissues by aliphatic nitrosomethylalkylamines shows organ specificity. Shorter chain compounds (C1-C5) correlate with liver and esophageal carcinogenicity, while longer chains show limited DNA modification.
Area of Science:
- Toxicology and Carcinogenesis
- Molecular Biology
- Organic Chemistry
Background:
- Aliphatic nitrosomethylalkylamines are known carcinogens exhibiting specific organ targeting in rats, primarily affecting the liver, esophagus, and bladder.
- Understanding the mechanism of carcinogenicity and organ specificity is crucial for risk assessment and prevention strategies.
Purpose of the Study:
- To investigate the relationship between DNA methylation levels and the organ-specific carcinogenicity of a series of aliphatic nitrosomethylalkylamines in rats.
- To determine the extent of DNA methylation in the liver, esophagus, and bladder following exposure to 12 different homologues.
Main Methods:
- Administration of a single oral dose of 12 aliphatic nitrosomethylalkylamine homologues (C1-C12) to rats.
- Quantification of methylpurines (7-methylguanine and O6-methylguanine) in liver, esophageal, and bladder DNA using cation-exchange high-performance liquid chromatography with fluorescence detection.
- Correlation of DNA methylation levels with known carcinogenicity data for each compound.
Main Results:
- Highest hepatic DNA methylation was observed with N-nitrosodimethylamine (NDMA, C1) and N-nitrosoethylmethylamine (NEMA, C2), potent hepatocarcinogens.
- Liver DNA methylation decreased with increasing chain length from C1 to C5; higher homologues (C6-C12) showed methylation levels insufficient to explain hepatocarcinogenicity.
- Esophageal DNA methylation closely paralleled carcinogenicity, with C4 and C5 being the most effective agents. Bladder DNA methylation was minimal and showed no correlation with carcinogenicity.
Conclusions:
- For shorter chain homologues (C1-C5), DNA methylation initiated by hydroxylation at the alpha-carbon may be a key mechanism in malignant transformation.
- For longer chain homologues (C6-C12), DNA modification alone is insufficient to explain their carcinogenicity and complex tissue specificity.
- The study highlights the differential impact of DNA methylation across various organs, contributing to the understanding of nitrosamine-induced carcinogenesis.