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A constitutive deficiency in the monooxygenase system of spontaneous mouse liver tumors
Abstract:
Exposure to chemical carcinogens evokes a population of altered hepatocytes that demonstrates significantly diminished monooxygenase activity. It has been suggested that this alteration permits the target cell to escape the toxic effects of the carcinogen and proliferate. In an attempt to determine whether this enzyme defect has broader implications for the carcinogenic process, we examined the monooxygenase system and additional components of spontaneous hepatocellular tumors in mice with a genetic predisposition to tumorigenesis. These tumors uniformly demonstrated a significant deficit in cytochrome P-450 and aminopyrine N-demethylase, despite the absence of known carcinogens, toxins, or promoting agents in their environment. Tumors of similar histiotype induced by a small, single neonatal administration of diethylnitrosamine demonstrated identical alterations. This report, therefore, suggests a strong link between a genetic program for tumorigenesis and a deficit in the monooxygenase system in spontaneous tumors. Further, it reveals that a toxic-selective environment is not required for the expansion of the cell population that possesses this phenotype.
Insights
Hepatocellular tumors, even spontaneous ones, show reduced monooxygenase activity. This enzyme deficit is linked to a genetic predisposition for cancer, not just carcinogen exposure.
Area of Science:
- Hepatocellular carcinoma research
- Carcinogenesis mechanisms
- Enzyme activity in tumors
Background:
- Chemical carcinogen exposure alters hepatocytes, reducing monooxygenase activity.
- This alteration may allow cells to evade toxins and proliferate.
- The role of enzyme defects in broader carcinogenic processes requires investigation.
Purpose of the Study:
- To investigate the monooxygenase system in spontaneous hepatocellular tumors.
- To determine if enzyme deficits are linked to genetic tumorigenesis predisposition.
- To compare enzyme activity in spontaneous vs. chemically induced tumors.
Main Methods:
- Examined monooxygenase system components in spontaneous mouse liver tumors.
- Analyzed tumors from mice with a genetic predisposition to tumorigenesis.
- Compared enzyme activity in spontaneous tumors with those induced by diethylnitrosamine.
Main Results:
- Spontaneous tumors uniformly showed deficits in cytochrome P-450 and aminopyrine N-demethylase.
- These enzyme deficits occurred without exposure to carcinogens, toxins, or promoters.
- Diethylnitrosamine-induced tumors exhibited identical alterations in the monooxygenase system.
Conclusions:
- A strong link exists between genetic predisposition for tumorigenesis and monooxygenase system deficits in spontaneous tumors.
- A toxic-selective environment is not necessary for the proliferation of cells with this enzyme defect.
- Enzyme deficits may be an intrinsic feature of a genetic cancer program.