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Heme enzyme patterns in genetically and chemically induced mouse liver tumors
Abstract:
Chemically induced rat hepatocyte nodules and hepatomas have repeatedly been shown to be deficient in Phase I drug-metabolizing enzymes. Some of these reduced activities are attributable to a diminution of the heme-containing terminal electron acceptor, cytochrome P-450. We recently demonstrated that spontaneous mouse liver tumors exhibit the same deficiency. Therefore, chemically induced and spontaneous liver tumors share common metabolic alterations which are likely to represent intrinsic characteristics of the tumorigenic process and are independent of its etiology. To determine whether the cytochrome P-450 deficit was the result of an altered heme metabolism, we quantitated four heme-containing proteins in normal mouse liver, spontaneous mouse liver tumors, and those induced by a single injection of diethylnitrosamine: cytochrome P-450; cytochrome b5; tryptophan 2,3-dioxygenase (EC 1.13.11.11); and catalase (EC 1.11.1.6). The amounts of these components in spontaneous tumors relative to normal liver were 0.35, 0.68, 0.76, and 0.51, respectively. Similar values were obtained with chemically induced tumors. The enzymes delta-aminolevulinic acid synthase (EC 2.3.1.37), the rate-limiting enzyme in the heme synthetic pathway, and heme oxygenase (EC 1.14.99.3), a degradative enzyme, were also quantitated. The amounts of these enzymes in spontaneous tumor relative to liver were 0.49 and 1.51, respectively. Again, similar values were observed for the chemically induced tumors. Alteration of the latter two enzyme activities may be sufficient for the altered hemoprotein patterns seen in mouse liver tumors. Further, this pattern of metabolic alteration is common to both chemically induced and spontaneous tumors. Thus, tumor resistance to cytotoxic agents activated by the monooxygenase system is not necessarily induced by exposure to these agents, nor as a result of selection.
Insights
Liver tumors, both spontaneous and chemically induced, show reduced cytochrome P-450, a key drug-metabolizing enzyme. This deficiency stems from altered heme metabolism, specifically changes in heme synthesis and degradation enzymes, impacting tumor characteristics.
Area of Science:
- Biochemistry
- Oncology
- Drug Metabolism
Background:
- Hepatocyte nodules and hepatomas often exhibit deficiencies in Phase I drug-metabolizing enzymes, including cytochrome P-450.
- This reduction in cytochrome P-450 activity is observed in both chemically induced and spontaneous liver tumors in rodents.
- These shared metabolic alterations suggest intrinsic characteristics of tumorigenesis, independent of the inducing agent.
Purpose of the Study:
- To investigate whether the cytochrome P-450 deficit in liver tumors results from altered heme metabolism.
- To compare the levels of key heme-containing proteins and enzymes involved in heme synthesis and degradation in normal liver and tumor tissues.
Main Methods:
- Quantification of heme-containing proteins: cytochrome P-450, cytochrome b5, tryptophan 2,3-dioxygenase, and catalase.
- Enzymatic assays for delta-aminolevulinic acid synthase (heme synthesis) and heme oxygenase (heme degradation).
- Comparison of these components in normal mouse liver, spontaneous mouse liver tumors, and diethylnitrosamine-induced mouse liver tumors.
Main Results:
- Spontaneous and chemically induced liver tumors showed significantly reduced levels of cytochrome P-450 (0.35 relative to normal liver).
- Other heme-containing proteins like cytochrome b5, tryptophan 2,3-dioxygenase, and catalase were also altered (0.68, 0.76, and 0.51, respectively).
- Tumors exhibited decreased delta-aminolevulinic acid synthase (0.49) and increased heme oxygenase (1.51), indicating altered heme turnover.
Conclusions:
- Altered heme metabolism, specifically changes in heme synthesis and degradation enzyme activities, likely underlies the hemoprotein deficits observed in mouse liver tumors.
- The observed metabolic alterations are common to both spontaneous and chemically induced tumors, suggesting a fundamental characteristic of the tumorigenic process.
- Tumor resistance to certain cytotoxic agents activated by monooxygenases may not solely be a result of exposure or selection, but rather linked to intrinsic metabolic changes.