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Microsomal metabolism of chemical carcinogens in animals and man
Abstract:
As the first step in the interaction between chemical carcinogen and cell, it has been recognized that most carcinogens, being chemically inert, must be metabolically converted into reactive, electrophilic 'ultimate carcinogens'. Ironically, the enzymes that activate carcinogens are the same microsomal, drug-metabolizing enzymes, mostly mixed-function oxidases, whose primary function is the detoxification and disposal of foreign chemicals. From the limited data available, it appears that, qualitatively, animals and man metabolize carcinogens via very similar pathways. However, in animals as well as in man there are marked species-related and individual differences in the basal levels of microsomal metabolism as well as in its inducibility. Therefore, the extrapolation to man of existing animal data on metabolic activation and carcinogenesis of chemicals is at present impossible. However, it might be possible to detect 'high-risk' individuals, i.e., individuals who might be especially endangered by exposure to environmental carcinogens due to their high rate of metabolism (for instance, some cigarette smokers), by determinations of human microsomal metabolism in vitro, using human leucocytes, or in vivo, employing safe drugs which are metabolized in a similar way to carcinogens, as indirect indices for individual variations in microsomal metabolism.
Insights
Most chemical carcinogens require metabolic activation by enzymes into reactive forms. Individual differences in these metabolic pathways mean animal data cannot predict human cancer risk, but may identify susceptible individuals.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Chemical carcinogens are often inert and require metabolic activation to become reactive 'ultimate carcinogens'.
- Microsomal drug-metabolizing enzymes, primarily mixed-function oxidases, are responsible for this activation, despite their main role in detoxification.
- Carcinogen metabolism pathways are qualitatively similar in animals and humans, but quantitative differences exist.
Purpose of the Study:
- To highlight the challenges in extrapolating animal carcinogen metabolism data to humans.
- To explore methods for identifying individuals at higher risk from environmental carcinogens based on their metabolic profiles.
Main Methods:
- Review of existing data on carcinogen metabolism in animals and humans.
- Discussion of in vitro (leukocyte metabolism) and in vivo (safe drug metabolism) methods to assess individual microsomal metabolism.
Main Results:
- Significant species-related and individual variations in basal and inducible microsomal metabolism levels are observed.
- Direct extrapolation of animal carcinogen metabolism and carcinogenesis data to humans is currently not feasible.
- Individual metabolic rates can be assessed using indirect methods to identify high-risk individuals.
Conclusions:
- Understanding individual metabolic variations is crucial for accurate human risk assessment of environmental carcinogens.
- Identifying high-risk individuals, such as certain cigarette smokers with high metabolic rates, is possible through metabolic profiling.
- In vitro and in vivo assays offer potential for assessing individual susceptibility to carcinogens.