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Changes in drug-metabolizing enzymes of rats in ciprofibrate-induced hepatic nodules
Abstract:
1. Premalignant rat liver nodules produced in the resistant hepatocyte model, by exposure to carcinogenic chemicals (diethyl nitrosamine and 2-acetamidofluorene), and partial hepatectomy, exhibit decreased xenobiotic hydroxylase activities and increased conjugase activities, which are considered responsible for increased resistance to xenobiotic toxicity. 2. However, premalignant rat liver nodules generated by feeding the hypolipidaemic, peroxisomal proliferating drug, ciprofibrate, in a hypolipidaemic model, exhibit decreased hydroxylase activities but decreased conjugase activities also. 3. It is considered that reactive oxygen species (ROS) are generated in both the resistant hepatocyte model and in the hypolipidaemic model, resulting in lipid peroxidation, loss of haem, cytochromes and hydroxylase activities. 4. However, whereas there is a rebounding compensation of conjugase enzymes in the resistant hepatocyte model, this does not occur with the hypolipidaemic model, as peroxidation is probably persistent and the conjugases are continuously destroyed.
Insights
Premalignant liver nodules show varying enzyme activity changes depending on their origin. Resistant hepatocyte models recover conjugase activity, unlike hypolipidaemic models where persistent damage hinders recovery.
Area of Science:
- Hepatology
- Toxicology
- Biochemistry
Background:
- Premalignant liver nodules develop differently based on induction methods.
- Understanding enzyme activity changes is crucial for predicting drug resistance and toxicity.
Purpose of the Study:
- To compare xenobiotic metabolism enzyme activities in premalignant liver nodules induced by different models.
- To investigate the role of reactive oxygen species (ROS) and lipid peroxidation in these changes.
Main Methods:
- Induction of premalignant rat liver nodules using the resistant hepatocyte model (carcinogens, partial hepatectomy) and the hypolipidaemic model (ciprofibrate).
- Assay of xenobiotic hydroxylase and conjugase enzyme activities.
- Evaluation of lipid peroxidation and reactive oxygen species generation.
Main Results:
- Resistant hepatocyte model nodules showed decreased hydroxylase and increased conjugase activities, conferring resistance.
- Hypolipidaemic model nodules exhibited decreased hydroxylase and decreased conjugase activities.
- Both models involved ROS generation and lipid peroxidation, impacting hydroxylase activities.
- Conjugase activity rebounded in the resistant hepatocyte model but not in the hypolipidaemic model due to persistent peroxidation.
Conclusions:
- Different induction methods lead to distinct alterations in xenobiotic metabolism enzymes within premalignant liver nodules.
- Persistent oxidative stress and lipid peroxidation in the hypolipidaemic model prevent the compensatory increase in conjugase activity observed in the resistant hepatocyte model.