Activities of Polycyclic Hydrocarbon Activating and Inactivating Enzymes in Human Lungs of Smokers, Non-Smokers, Lung-Cancer and Non-Cancer Patients
Human lungs are an important target organ for environmental carcinogenic polycyclic hydrocarbons (PAH), which can be metabolised by microsomal monooxygenases (MO) to mutagenic epoxides. The concentrations within the cells of these reactive epoxides, which are suspected ultimate carcinogens, will be controlled not only by the MO activities, but also by the epoxide inactivating epoxide hydratase (EH) and glutathione-S-transferase (GT) activities. To our knowledge no data exist on these enzyme activities in human lungs.
Therefore, we have investigated these enzyme activities and studied whether a correlation exists between these epoxide forming and inactivating enzyme activities and the occurrence of lung cancer by measuring these enzyme activities in 47 samples from lungs of smokers, non-smokers, lung-cancer and non-cancer patients. Using standard assays no MO activity could be detected, although the very sensitive assays with benzo(a)pyrene, 7-ethoxycoumarin, 7-ethoxyresorufm and biphenyl as substrates were used whilst these activities in rat lung microsomes used as positive controls were always clearly measurable. Evidence was obtained for the presence of a diffusible MO-inhibitor in human lung microsomes. Finally we succeded in measuring 7-ethoxycoumarin-0-dealkylase activity after modification of the assay. EH and GT activities were determined with benzo(a)pyrene 4,5-oxide, the latter was also measured with 2,4-dinitrochloro-benzene as substrate.
Considerable interindividual variations in enzyme activities were observed. However, no significant differences were found when the enzyme activities in lungs from non-cancer patients and non-smokers were compared with those in lung cancer patients.
The substrate specificity of human lung epoxide hydratase investigated using K-region epoxides of various PAH was similar to that in rat liver and in human, rat and mouse skin.
Key wordsEpoxide hydratase Glutathione-S-transferase Monooxygenase Lung Cancer
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