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Quantifying Single Microvessel Permeability in Isolated Blood-perfused Rat Lung Preparation
Published on: June 30, 2014
Metabolism of benzo[a]pyrene by the isolated perfused rabbit lung
Abstract:
The metabolism of benzo[a]pyrene (BP) was studied in the isolated perfused rabbit lung and in rabbit pulmonary microsomes. Pretreatment of rabbits with 3-methylcholanthrene did not increase the metabolism of BP by microsomal preparations, and the pretreatment did not induce cytochrome P-448 in pulmonary microsomes. In the isolated perfused lung, BP was metabolized at a rate of about 6 nmol/min/g of lung. The intermediate arene oxides formed from BP in the isolated perfused lung were metabolized nonoxidatively by epoxide hydrase and glutathione S-transferases. The rates of the latter reactions were at least an order of magnitude less than the overall rate of metabolism. Pretreatment of the animals with 3-methylcholanthrene increased only the apparent rate of the epoxide hydrase reaction. In the isolated perfused lung, BP and some of its less polar metabolites (i.e., quinones and phenolic derivatives) were preferentially partitioned into lung tissue, precluding accurate measurement of metabolic rates by analysis of the perfusion medium alone. Covalent binding of BP-derived radioactivity to lung tissue occurred, but relatively high variability in this parameter in lungs from 3-methylcholanthrene-pretreated animals did not allow measurement of a significant difference from control lungs.
Insights
This study investigated benzo[a]pyrene metabolism in rabbit lungs. While 3-methylcholanthrene pretreatment didn't boost microsomal metabolism, it enhanced epoxide hydrase activity in perfused lungs.
Area of Science:
- Environmental Toxicology
- Pharmacokinetics
- Pulmonary Metabolism
Background:
- Benzo[a]pyrene (BP) is a polycyclic aromatic hydrocarbon found in the environment.
- Understanding BP metabolism is crucial for assessing its toxicological impact, particularly in the lungs.
- Pulmonary metabolism plays a significant role in the bioactivation and detoxification of xenobiotics.
Purpose of the Study:
- To investigate the metabolism of benzo[a]pyrene (BP) in isolated perfused rabbit lungs and pulmonary microsomes.
- To determine the effect of 3-methylcholanthrene (3-MC) pretreatment on BP metabolism and associated enzyme induction.
- To characterize the pathways and rates of BP metabolism and metabolite partitioning within the lung.
Main Methods:
- Isolated perfused rabbit lung model to study BP metabolism in a physiologically relevant system.
- Rabbit pulmonary microsomes used to assess specific enzymatic activities.
- Analysis of BP and its metabolites in perfusion medium and lung tissue.
- Measurement of covalent binding of BP-derived radioactivity to lung tissue.
Main Results:
- BP was metabolized in the perfused lung at approximately 6 nmol/min/g.
- Arene oxides formed during BP metabolism were primarily detoxified by epoxide hydrase and glutathione S-transferases.
- 3-MC pretreatment did not induce cytochrome P-448 or increase BP metabolism in microsomes.
- 3-MC pretreatment selectively increased the epoxide hydrase reaction rate in perfused lungs.
- BP and its metabolites preferentially partitioned into lung tissue, complicating perfusion medium analysis.
- Covalent binding of BP metabolites to lung tissue showed high variability, preventing significant difference detection between control and pretreated groups.
Conclusions:
- Pulmonary metabolism of BP involves both oxidative and non-oxidative pathways, with non-oxidative routes being significant.
- 3-MC pretreatment differentially affects BP metabolism, enhancing epoxide hydrase activity without inducing microsomal P450s.
- Lung tissue partitioning of BP and its metabolites influences overall metabolic assessment.
- Further investigation is needed to clarify the role of covalent binding and its variability.
