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Metabolism of 1,2-dimethylhydrazine by cultured human colon
Abstract:
The overall metabolism of 1,2-dimethylhydrazine, and organotropic colon carcinogen in rodents, has been studied using human colon explant cultures. The binding level of 1,2-dimethylhydrazine to DNA which in this study includes both reaction of metabolites with DNA and incorporation of radioactive metabolites into DNA, showed a 100-fold variation among the 120 people studied. When different anatomical colonic sites were compared, the highest mean binding levels were found in the ascending and sigmoid colon. No significant difference in the median and mean binding levels were observed in nontumorous colon obtained surgically from patients with colon cancer and colon obtained from immediate autopsy, but decreased mean binding levels were seen in tissues obtained by surgery from patients with non-cancerous colonic disorders. Several exogenous chemicals were found to modify the metabolism. When the colon explants were co-incubated with 1,2-dimethylhydrazine and these chemicals, the binding level of 1,2-dimethylhydrazine to DNA was (a) increased by either indole 3-carbinol or phenobarbital, (b) decreased with disulfiram, butylated hydroxytoluene, or taurodeoxycholic acid, and (c) unaltered by lithocholic acid.
Insights
Human colon explant studies reveal significant variations in 1,2-dimethylhydrazine DNA binding. Certain chemicals alter this binding, impacting colon cancer risk.
Area of Science:
- Biochemistry
- Toxicology
- Gastroenterology
Background:
- 1,2-dimethylhydrazine is a colon carcinogen in rodents.
- Understanding its metabolism in humans is crucial for cancer research.
- Human colon explant cultures provide a model for studying carcinogen metabolism.
Purpose of the Study:
- To investigate the metabolism and DNA binding of 1,2-dimethylhydrazine in human colon explants.
- To identify variations in binding levels across individuals and anatomical sites.
- To determine the effect of exogenous chemicals on 1,2-dimethylhydrazine metabolism.
Main Methods:
- Human colon explant cultures were used to study 1,2-dimethylhydrazine metabolism.
- DNA binding levels were quantified, including metabolite reaction and incorporation.
- Explants were co-incubated with 1,2-dimethylhydrazine and various exogenous chemicals.
Main Results:
- A 100-fold variation in 1,2-dimethylhydrazine DNA binding was observed among 120 individuals.
- The ascending and sigmoid colon showed the highest mean binding levels.
- Exogenous chemicals like indole 3-carbinol and phenobarbital increased binding, while disulfiram and BHT decreased it.
Conclusions:
- Individual variability in 1,2-dimethylhydrazine DNA binding is substantial.
- Anatomical site influences binding levels within the colon.
- Modulation of 1,2-dimethylhydrazine metabolism by exogenous chemicals offers potential targets for intervention.