In vitro covalent binding of new brain tracer, para-125I-amphetamine, to rat liver and lung microsomes

Journal Article · Mon Jan 01 00:00:00 EST 1990 · Drug and Chemical Toxicology; (USA)

DOI:https://doi.org/10.3109/01480549009032290· OSTI ID:5893631

Joulin, Y; Delaforge, M; Hoellinger, H; Moretti, J L; Sonnier, M; Cesaro, P ^[1]

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1. CHU H. Mondor, Creteil (France)

p-125I-amphetamine (I-Amp) is retained significantly in liver and lung during brain tomoscintigraphy. To attempt to explain this clinical observation, we have investigated the interaction of I-Amp with rat liver and lung microsomal proteins. Studies using spectral shift technique indicate that low concentration of I-Amp gives a type I complex and high concentration appears very stable type II complex with cytochrome P-450 Fe III. In the presence of NADPH, I-Amp gives rise to a 455 nm absorbing complex with similar properties to the Fe-RNO complexes. This complex formation was greatly enhanced with phenobarbital treated liver microsomes. The in vitro binding study shows that I-Amp and/or its metabolites was covalently bound to macromolecules in the presence of the molecular oxygen and NADPH-generating system. Incubation in the presence of glutathione, cystein and radical scavengers decreases binding. Mixed function oxydase (MFO) inhibitors diminish the amount of covalent binding and alter the extent of metabolite formation. The total covalent binding level increased with liver microsomes from PB pretreated rats as it was observed with the 455nm complex formation. The radioactivity distribution on microsomal proteins was examinated with SDS polyacrylamide gel electrophoresis and autoradiography. This experiment proves that the radiolabelled compounds are bound on the cytochrome P-450. The radioactivity bound increased when the PB induced rat liver microsomes were used. All these results indicate that I-Amp was activated by an oxydative process dependent on the MFO system which suggests a N-oxydation of I-Amp and the formation of reactive entities which covalently bind to proteins.

• OSTI ID: 5893631
• Journal Information: Drug and Chemical Toxicology; (USA), Vol. 13:4; ISSN 0148-0545
• Country of Publication: United States
• Language: English

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