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Oxidative biotransformation of benzo(a)pyrene by human lung microsomal fractions prepared from surgical specimens
Abstract:
1. Microsomal fractions were prepared from 15--50 g specimens of human lung tissue (mostly alveolar) obtained at surgical resections of 13 middle-aged male patients suffering from different pulmonary tumours. Marker enzyme assays indicated that the frations contained about 25% of the endoplasmic reticulum of the homogenate and about 10% of its mitochondrial membranes. 2. The content of cytochrome b5 corresponded to that of rodent lung microsomes, whereas the apparent content of cytochrom P-450 was much lower. 3. The extent of benzo(a)pyrene metabolism varied 13-fold between individuals in the group and was not detectable in about 40% of the cases. 4. The dihydrodiols as % of total metabolites formed was higher than in laboratory animals, the 7,8-dihydrodiol in most cases amounting to more than 40% of total dihydrodiols. 5. The apparent rate of hydroxylation was stimulated by 1 mM 2-diethylaminothyl 2,2-diphenylvalerate and by 1 mM 1,2-oxy-3,3,3-trichloropropane, but inhibited moderately by 0.1 mM metyrapone and extensively by 0.05 mM 7,8-benzoflavone. 6. Ethoxyresorufin deethylation qualitatively paralleled benzo(a)pyrene hydroxylation among individuals.
Insights
Human lung tissue exhibits variable benzo(a)pyrene metabolism, with higher dihydrodiol formation than in animals. This variability impacts drug metabolism and cancer risk assessment in pulmonary tumor patients.
Area of Science:
- Biochemistry
- Toxicology
- Pulmonology
Background:
- Human lung microsomes are crucial for metabolizing environmental pollutants and xenobiotics.
- Understanding inter-individual variability in lung metabolism is vital for assessing cancer risk and drug efficacy.
Purpose of the Study:
- To characterize the metabolic capacity of human lung microsomes from patients with pulmonary tumors.
- To investigate the metabolism of benzo(a)pyrene and its relationship with other metabolic pathways.
Main Methods:
- Preparation of microsomal fractions from human lung tissue obtained during surgical resections.
- Assay of marker enzymes to determine microsomal composition.
- Quantification of benzo(a)pyrene metabolites and ethoxyresorufin deethylation.
Main Results:
- Human lung microsomes showed lower cytochrome P-450 content compared to rodent lung microsomes.
- Significant inter-individual variability (13-fold) in benzo(a)pyrene metabolism was observed, with undetectable levels in 40% of cases.
- Higher formation of dihydrodiols, particularly 7,8-dihydrodiol, was noted compared to laboratory animals.
Conclusions:
- Human lung metabolic activity, specifically benzo(a)pyrene hydroxylation, is highly variable among individuals with pulmonary tumors.
- The elevated dihydrodiol formation suggests a distinct metabolic profile in human lungs that may influence carcinogen activation.
- These findings highlight the importance of considering individual metabolic differences in lung cancer research and therapeutic strategies.