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Xenobiotic metabolizing enzymes in genetically and chemically initiated mouse liver tumors
Abstract:
Chemically induced rat liver nodules and cancers characteristically demonstrate a limited capacity to activate xenobiotics to reactive species mainly because of decreased amounts of cytochrome P-450. These lesions also show enhancement of xenobiotic detoxication by such mechanisms as enzymic conjugation or reduction of cytotoxic species. We recently demonstrated a similar pattern of metabolic alteration in spontaneous mouse liver tumors. These findings suggested that certain phenotypic alterations attributed to chronic chemical exposure are inherent in the genetic program for carcinogenesis, and that they may arise independently of chronic exposure. To extend that study, we examined spontaneous and diethylnitrosamine-induced mouse liver tumors for nine enzyme activities commonly reported to be altered in chemically induced rat liver nodules and cancers. The activities of benzo(a)pyrene monooxygenase (EC 1.14.14.1), aminopyrene demethylase, cytochrome P-450 reductase, epoxide hydrolase (EC 3.3.2.3), and UDPglucuronosyl transferase (EC 2.4.1.17) in microsomes from spontaneous tumors relative to those from normal liver were 0.25, 0.43, 1.27, 0.90, and 0.51, respectively. Similar values were obtained with microsomes from chemically induced tumors. The activities of DT-diaphorase (EC 1.6.99.2), glutathione reductase (EC 1.6.4.2), glutathione S-transferase (EC 2.5.1.18), and glutathione peroxidase (EC 1.11.1.9) in cytosol from spontaneous tumors relative to cytosol from normal liver were 2.24, 2.0, 2.43, and 0.31, respectively. Similar values were obtained with cytosol from chemically induced tumors. These results demonstrated that a significant portion of the enzymic phenotype observed in chemically induced rat liver nodules and cancers, which may confer resistance to cytotoxic chemicals, is manifest in spontaneous and chemically induced mouse liver tumors. Further, initiated cells that exhibit this phenotype replicated and progressed in the absence of continued chemical selection.
Insights
Liver tumors, both spontaneous and chemically induced, share similar enzyme activity patterns. These alterations in xenobiotic metabolism may arise from genetic programming rather than solely from chemical exposure, influencing tumor progression.
Area of Science:
- Biochemistry
- Toxicology
- Carcinogenesis
Background:
- Chemically induced rat liver tumors often show reduced xenobiotic activation due to lower cytochrome P-450 levels.
- These tumors also exhibit enhanced detoxification pathways, suggesting a protective metabolic phenotype.
- Previous studies indicated similar metabolic alterations in spontaneous mouse liver tumors.
Purpose of the Study:
- To investigate if metabolic alterations observed in chemically induced rodent liver tumors are also present in spontaneous mouse liver tumors.
- To compare enzyme activities related to xenobiotic metabolism and detoxification in both spontaneous and chemically induced mouse liver tumors.
- To determine if these phenotypic changes are inherent to carcinogenesis or solely a result of chemical exposure.
Main Methods:
- Assessed nine specific enzyme activities in liver microsomes and cytosol from spontaneous and diethylnitrosamine-induced mouse tumors.
- Measured activities including benzo(a)pyrene monooxygenase, aminopyrene demethylase, cytochrome P-450 reductase, epoxide hydrolase, UDP-glucuronosyl transferase, DT-diaphorase, glutathione reductase, glutathione S-transferase, and glutathione peroxidase.
- Compared enzyme activities in tumor tissues to those in normal liver tissues.
Main Results:
- Spontaneous mouse liver tumors showed significantly decreased activities for benzo(a)pyrene monooxygenase (0.25x) and UDP-glucuronosyl transferase (0.51x) compared to normal liver.
- Activities of DT-diaphorase (2.24x), glutathione reductase (2.0x), and glutathione S-transferase (2.43x) were significantly elevated in spontaneous tumors.
- Chemically induced tumors exhibited similar patterns of altered enzyme activities, supporting the conserved nature of this metabolic phenotype.
Conclusions:
- A significant portion of the enzyme activity profile associated with chemically induced rat liver tumors, potentially conferring resistance to cytotoxic agents, is also present in spontaneous and chemically induced mouse liver tumors.
- These findings suggest that initiated cells can acquire a protective metabolic phenotype independently of chronic chemical exposure.
- The observed phenotype may play a role in the replication and progression of initiated cells during carcinogenesis, even without continued chemical selection.