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Alteration of drug biotransformation by interferon and host defence mechanism
1Department of Pharmacology, Faculty of Medicine, National University of Singapore.
Abstract:
It has been demonstrated that the liver loses its capacity to metabolise and eliminate drugs during viral infection or during the operation of host defence mechanisms. This loss in drug metabolism is due to the loss of the cytochrome P-450 component of the mixed function oxidase (the enzyme system primarily responsible for the oxidation of drugs, carcinogens and certain classes of endogenous substances such as steroids, fatty acids and prostaglandins). At present we have identified interferon and factors such as interleukin-1, interleukin-6 and tumour necrosis factor, released from Kupffer cells, as major mediators of the loss. The depression that occurs during viral infection is mediated via the production of interferon. This action of interferon requires the synthesis of an intermediate/s yet to be identified. The molecular mechanism for the decrease in cytochrome P-450 mediated drug metabolism during episodes of viral infections is caused by an interferon-mediated loss in mRNA and subsequent cytochrome P-450 synthesis in the liver.
Insights
Viral infections impair liver drug metabolism by reducing cytochrome P-450. This occurs through an interferon-mediated decrease in messenger RNA (mRNA) and subsequent enzyme synthesis.
Area of Science:
- Pharmacology
- Hepatology
- Immunology
Background:
- Liver drug metabolism is crucial for drug elimination.
- Viral infections and host immune responses can disrupt normal liver function.
- Cytochrome P-450 enzymes are key players in drug metabolism within the liver.
Purpose of the Study:
- To investigate the mechanisms behind the loss of liver drug metabolism during viral infections.
- To identify the mediators responsible for the depression of cytochrome P-450 activity.
- To elucidate the molecular pathways involved in impaired drug metabolism.
Main Methods:
- Analysis of liver tissue during viral infection models.
- Identification of cytokines and signaling molecules involved.
- Measurement of cytochrome P-450 levels and mRNA expression.
Main Results:
- Viral infections lead to a significant decrease in liver drug metabolism.
- Interferon, interleukin-1, interleukin-6, and tumor necrosis factor are identified as key mediators.
- The process involves an interferon-mediated reduction in cytochrome P-450 mRNA and synthesis.
Conclusions:
- Interferon plays a central role in suppressing cytochrome P-450 mediated drug metabolism during viral infections.
- The observed decrease in drug metabolism is linked to reduced mRNA and enzyme synthesis.
- Understanding these mechanisms is vital for managing drug therapy during infections.