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Toxicity and enzyme-inducing effect of the antiviral compound mopyridone in mice
1Institute of Physiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Abstract:
Mopyridone (CAS 82822-14-8, MP) is a new antiviral compound with low acute toxicity in mice. Phenobarbital (PB) induction did not alter MP oral acute toxicity, while methylcholanthrene (MC) and dexamethasone (DEX) induction increased it. MP (1/10 of LD50, 5 days) increased aniline hydroxylase activity (by 158%) and cytochrome P-450 content (by 43%), but has no significant effect on liver N-demethylase activity (ethylmorphine N-demethylase, amidopyrine N-demethylase and benzphetamine N-demethylase) in mouse liver 10,000 x g supernatant. The inducing effect of MP was similar to the effect of MC and differed from the effect of PB. The combination MP + PB exerted an additive inducing effect on aniline hydroxylase (by 390%) and cytochrome P-450 content (by 183%) without affecting PB induced N-demethylases. The character of the MP + PB interaction was similar to that of the MC + PB interaction and suggested different inducing mechanisms of MP and PB. The participation of some cytochrome P-450 isozymes, induced by MC and DEX, in biotransformation of MP to more toxic product(s) was suggested.
Insights
Mopyridone (MP), an antiviral, has low acute toxicity. However, methylcholanthrene (MC) and dexamethasone (DEX) increase MP toxicity, suggesting specific cytochrome P-450 isozymes mediate MP biotransformation.
Area of Science:
- Pharmacology
- Toxicology
- Drug Metabolism
Background:
- Mopyridone (MP) is a novel antiviral agent.
- Understanding MP's interaction with drug-metabolizing enzymes is crucial for its clinical application.
Purpose of the Study:
- To investigate the effect of MP on mouse liver enzyme activities.
- To determine the influence of enzyme inducers (phenobarbital, methylcholanthrene, dexamethasone) on MP toxicity and metabolism.
- To elucidate the mechanisms underlying MP-induced toxicity.
Main Methods:
- Acute toxicity testing of MP in mice.
- Administration of enzyme inducers (PB, MC, DEX) prior to MP exposure.
- Measurement of aniline hydroxylase and N-demethylase activities in mouse liver 10,000 x g supernatant.
- Quantification of cytochrome P-450 content.
Main Results:
- MP exhibits low acute toxicity, but co-administration with MC or DEX significantly increases toxicity.
- MP administration induces aniline hydroxylase activity and cytochrome P-450 content.
- MP does not significantly affect N-demethylase activities.
- Combined MP and PB treatment shows additive induction of aniline hydroxylase and cytochrome P-450, distinct from PB's effects alone.
Conclusions:
- MP's toxicity profile is influenced by specific cytochrome P-450 isozymes, particularly those induced by MC and DEX.
- MP and PB appear to have different enzyme induction mechanisms.
- Further research is needed to identify the specific P450 isozymes involved in MP biotransformation and toxicity.