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Effect of a mixed function oxidase inducer and inhibitor on monocrotaline pyrrole pneumotoxicity
Abstract:
Monocrotaline (MCT) produces vascular injury to the lung, pulmonary hypertension, and right ventricular hypertrophy when injected into rats. It is well established that the pneumotoxicity of MCT depends on its hepatic bioactivation to monocrotaline pyrrole (MCTP) and perhaps other toxic metabolites. To test whether MCTP requires further bioactivation, we synthesized this metabolite chemically, confirmed its structure using fast-atom bombardment-mass spectrometry and nuclear magnetic resonance, and injected it into rats previously treated with an inducer or inhibitor of MFOs. Pretreatment with either phenobarbital or SKF-525A did not alter the pneumotoxic effects of an intravenous injection of MCTP. Rats given the same intravenous dose of either MCT, MCT N-oxide, or MCTP responded with toxicity only to MCTP. MCTP added to rat serum in vitro resulted in a color change (Amax = 477 nm) that developed over several seconds, an observation consistent with degradation of MCTP in serum. To explore the possibility that aqueous degradation products might contribute to its toxicity, the same intravenous dose of MCTP was administered to rats in N,N-dimethylformamide (DMF), serum, or saline. Only MCTP administered in in DMF resulted in toxicity. These results support the contention that MCT requires metabolism to MCTP to produce pneumotoxicity and that exposure to aqueous media renders MCTP incapable of causing lung injury.
Insights
Monocrotaline (MCT) causes lung injury, but its toxic metabolite, monocrotaline pyrrole (MCTP), does not require further bioactivation. MCTP is toxic only when protected from aqueous degradation, indicating MCTP is the active toxic agent.
Area of Science:
- Toxicology
- Pharmacology
- Pulmonary Medicine
Background:
- Monocrotaline (MCT) is known to cause lung vascular injury and pulmonary hypertension.
- The pneumotoxicity of MCT is attributed to its hepatic bioactivation into monocrotaline pyrrole (MCTP).
Purpose of the Study:
- To determine if MCTP requires further bioactivation to exert its toxic effects.
- To investigate the role of aqueous degradation in MCTP's toxicity.
Main Methods:
- MCTP was chemically synthesized and its structure confirmed.
- Rats were pretreated with mixed-function oxidase (MFO) inducers or inhibitors before MCTP administration.
- MCTP was administered intravenously in different vehicles (DMF, serum, saline) to assess toxicity.
Main Results:
- MCTP did not require further bioactivation by MFOs to cause pneumotoxicity.
- Intravenous injection of MCTP, but not MCT or MCT N-oxide, resulted in toxicity.
- MCTP rapidly degraded in aqueous media (serum, saline) and lost toxicity, while toxicity was retained in N,N-dimethylformamide (DMF).
Conclusions:
- MCTP is the primary toxic metabolite responsible for MCT-induced pneumotoxicity.
- Aqueous degradation inactivates MCTP, suggesting that its toxicity is mediated by the intact molecule, not its degradation products.