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Heme enzyme patterns in rat liver nodules and tumors
Abstract:
Chemically induced rat hepatocyte nodules and carcinomas have a reduced capacity to oxidize drugs. The reduction in monoxygenase activity results largely from the partial loss of cytochrome P-450, a heme-containing terminal electron acceptor. To determine whether the cytochrome P-450 deficit was indicative of an altered heme metabolism, we quantitated four heme-containing proteins in normal rat liver and in rat liver nodules and cancers induced by 2-acetylaminofluorene or diethyl-nitrosamine: cytochrome P-450; cytochrome bs; catalase (EC 1.11.1.6); and tryptophan 2,3-dioxygenase (EC 1.13.11.11). The amounts of these components in nodules were 45%, 88%, 50%, and 59% of normal liver, respectively; in 2-acetylaminofluorene-induced cancers, 65%, 74%, 64%, and 65%, respectively; and in diethylnitrosamine-induced cancers, 40%, 69%, 56%, and 52%. 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 nodules were 95% and 138% of normal liver, respectively, whereas in 2-acetylaminofluorene-induced cancers, they were 47% and 233%, and in diethylnitrosamine-induced cancers, they were 50% and 175%. These data indicate that four nonmitochondrial liver hemoproteins were diminished to about the same extent in hepatic nodules and cancers. Nodules and cancers also demonstrated an increased capacity for heme degradation, while cancers also demonstrated a decreased capacity for heme synthesis. Thus, the resistance of nodules and tumors to P-450-activated cytotoxic agents may ultimately result from a disturbance in heme metabolism.
Insights
Hepatocyte nodules and cancers show reduced drug oxidation due to lower cytochrome P-450. This study reveals altered heme metabolism, with increased degradation and decreased synthesis in tumors, impacting drug resistance.
Area of Science:
- Biochemistry
- Hepatology
- Toxicology
Background:
- Chemically induced rat liver nodules and carcinomas exhibit diminished drug-oxidizing capacity.
- This reduction is primarily linked to a loss of cytochrome P-450, a critical heme-containing enzyme involved in drug metabolism.
Purpose of the Study:
- To investigate if the observed cytochrome P-450 deficit in liver tumors reflects broader alterations in heme metabolism.
- To quantify key heme-containing proteins and enzymes involved in heme synthesis and degradation in normal liver, nodules, and cancers.
Main Methods:
- Quantification of four heme-containing proteins: cytochrome P-450, cytochrome b5, catalase, and tryptophan 2,3-dioxygenase.
- Measurement of delta-Aminolevulinic acid synthase (heme synthesis) and heme oxygenase (heme degradation) enzyme activities.
- Comparison of these components in normal rat liver versus chemically induced hepatocyte nodules and carcinomas.
Main Results:
- Four non-mitochondrial hemoproteins (cytochrome P-450, cytochrome b5, catalase, tryptophan 2,3-dioxygenase) were significantly reduced in nodules and cancers compared to normal liver.
- Hepatocyte nodules and cancers showed an increased capacity for heme degradation (higher heme oxygenase levels).
- Cancers exhibited a decreased capacity for heme synthesis (lower delta-Aminolevulinic acid synthase levels).
Conclusions:
- The data suggest a significant disturbance in heme metabolism underlies the development of chemically induced liver nodules and cancers.
- Altered heme metabolism, including increased degradation and decreased synthesis, may contribute to the reduced cytochrome P-450 levels.
- This metabolic shift could explain the observed resistance of these hepatic lesions to P-450-activated cytotoxic agents.