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Cytochrome P-450 in the activation and inactivation of carcinogens
Abstract:
The capacity of isolate mouse liver microsomes to alter the mutagenicity for bacteria of the primary carcinogen N-methyl-N'-nitro-N-nitrosoguanisine (MNNG) and the secondary one dimethylnitrosamine (DMN) was studied. Microsomal activation of DMN and inactivation of MNNG were decreased by protein- and protein-cholinedeficient diets and were increased by pretreatment with microsomal enzyme inducers. The decrease and increase paralleled the content of cytochrome P-450 present in the different microsomal preparations. With human liver microsomes of differing cytochrome P-450 contents similar correlation was obtained, whereas normal rat liver microsomes did not activate or inactivate DMN or MNNG. Oxidative demethylation of DMN by mouse liver microsomes and the activation of DMN to a mutagen followed similar kinetics. Both reactions were inhibited by carbon monoxide and the inhibition was maximally reversed by monochromatic light at 450 nm. These observations indicate that at least some carcinogens are activated or inactivated by the unspecific cytochrome P-450 dependent enzyme system, suggesting that the extent of this biotransformation may be one factor influencing human carcinogenesis.
Insights
Liver microsomes metabolize carcinogens like N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and dimethylnitrosamine (DMN). Cytochrome P-450 levels, influenced by diet and enzyme inducers, affect this activation and inactivation, impacting cancer risk.
Area of Science:
- Biochemistry
- Toxicology
- Carcinogenesis
Background:
- Carcinogen metabolism is crucial for understanding cancer development.
- Liver microsomes contain enzymes that can activate or inactivate chemical carcinogens.
- Cytochrome P-450 enzymes play a significant role in xenobiotic metabolism.
Purpose of the Study:
- To investigate the role of mouse liver microsomes in the mutagenicity of N-methyl-N itro-N-nitrosoguanidine (MNNG) and dimethylnitrosamine (DMN).
- To determine how dietary deficiencies and enzyme inducers affect microsomal activation/inactivation of these carcinogens.
- To correlate these metabolic changes with cytochrome P-450 content.
Main Methods:
- Isolated mouse liver microsomes were used to assess mutagenicity changes.
- Microsomal enzyme activity was modulated by protein/choline-deficient diets and enzyme inducers.
- Cytochrome P-450 content was quantified in microsomal preparations.
- Kinetic studies and inhibition experiments (carbon monoxide, light at 450 nm) were performed.
Main Results:
- Microsomal activation of DMN and inactivation of MNNG were reduced by deficient diets and increased by enzyme inducers.
- These changes directly correlated with cytochrome P-450 content.
- Human liver microsomes showed similar correlations, while rat liver microsomes were inactive.
- Oxidative demethylation of DMN and its mutagenic activation followed similar kinetics, inhibited by CO.
Conclusions:
- Cytochrome P-450 dependent enzymes are involved in the activation and inactivation of certain carcinogens.
- Dietary factors and enzyme induction can significantly alter carcinogen metabolism.
- The extent of carcinogen biotransformation by cytochrome P-450 is a potential factor in human carcinogenesis.