Effect of a mixed function oxidase inducer and inhibitor on monocrotaline pyrrole pneumotoxicity.
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.
D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D008171:Lung Diseases / Q000139:chemically induced*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism*; D016686:Monocrotaline / Q000031:analogs & derivatives; D014677:Pharmaceutical Vehicles; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D013329:Structure-Activity Relationship
D014677:Pharmaceutical Vehicles; D011763:Pyrrolizidine Alkaloids; C014114:monocrotaline pyrrole; D016686:Monocrotaline; D011335:Proadifen; D006899:Mixed Function Oxygenases; D010634:Phenobarbital