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[Effect of multiple peroral use of analgin on the liver monooxygenase system in the rat]
Abstract:
Analgin given repeatedly per os in dose 15 mg/kg to white male rats, causes changes in some indices of the liver NADPH-dependent mono-oxygenase system. At the end of the first month a decrease in the quantity of the microsomal protein was established as well as increase of the cytochrome's content P-450 and b5. The frequencies of cytochrome P-450-dependent biotransformations of substrates aminopyrine and aniline are also of different directions. At the end of the sixth month, because of multiple drug application all these indices are in the limits of the control values. A change in the catalytic features of cytochrome P-450, is established, which is expressed mainly by strongly decreased affinity to the substrates of first type. The Michaelis's constant Km for substrate aminopyrine depends on the duration of analgin introduction and increases up to 300% towards the control at the end of the sixth month.
Insights
Repeated administration of Analgin in rats alters liver enzymes, specifically the NADPH-dependent mono-oxygenase system. While initial changes occur, prolonged use normalizes some indices but reduces cytochrome P-450 affinity for certain substrates.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- The liver's NADPH-dependent mono-oxygenase system is crucial for metabolizing xenobiotics.
- Analgin (dipyrone) is a widely used analgesic and antipyretic agent.
- Understanding drug-induced alterations in hepatic enzyme systems is vital for assessing safety and efficacy.
Purpose of the Study:
- To investigate the effects of repeated Analgin administration on the rat liver NADPH-dependent mono-oxygenase system.
- To characterize changes in microsomal protein, cytochrome P-450, and cytochrome b5 content.
- To evaluate alterations in the biotransformation of specific substrates and the catalytic properties of cytochrome P-450.
Main Methods:
- Male Wistar rats were administered Analgin orally at 15 mg/kg daily.
- Liver microsomes were isolated at one and six months post-administration.
- Microsomal protein, cytochrome P-450, and cytochrome b5 levels were quantified.
- Enzyme kinetics, including Michaelis constant (Km) for aminopyrine, were determined.
Main Results:
- After one month, Analgin decreased microsomal protein but increased cytochrome P-450 and b5 levels.
- Substrate biotransformation rates for aminopyrine and aniline showed varied responses.
- By six months, most indices returned to control levels.
- A significant decrease in cytochrome P-450 affinity for certain substrates was observed, with Km for aminopyrine increasing up to 300%.
Conclusions:
- Repeated Analgin administration induces transient changes in rat liver microsomal enzymes.
- Prolonged exposure leads to adaptive changes, normalizing some parameters but altering enzyme kinetics.
- The reduced affinity of cytochrome P-450 for substrates suggests potential long-term metabolic consequences.