Monooxygenase, epoxide hydrolase, and glutathione-S-transferase activities in human lung. Variation between groups of bronchogenic carcinoma and non-cancer patients and interindividual differences.
Activities of microsomal monooxygenases (MO) and epoxide hydrolase (EH) and cytoplasmic glutathione-S-transferases (GST) will contribute to controlling the pool of reactive intermediates, enzymatically derived from polynuclear aromatic hydrocarbons (PAH) within the cells of target organs such as the human lung. Therefore, we studied what interindividual differences exist in these enzyme activities and whether there is a correlation between the activities of these epoxide forming and metabolizing enzymes in preparations from peripheral lung samples and the occurrence of bronchogenic carcinomas in smokers and non-smokers. 57 samples obtained from surgery were studied. Among them were 12 samples from non-smoking patients without cancer as a control group. It is not known whether this control group behaves, with respect to the investigated parameters, identically to fully healthy people, since in all cases indications existed which justified the removal of lung biopsies. Using very sensitive standard assays with benzo[a]pyrene, biphenyl, 7-ethoxyresorufin and 7-ethoxycoumarin as substrates, MO activity could only be determined as O-deethylation of 7-ethoxycoumarin and only after modification of the assay method. Evidence was obtained for the presence of a diffusible, but not dialysible, MO inhibitor in human lung microsomes. The MO activity (substrate: 7-ethoxycoumarin) in this fraction was extremely low in human (100-fold lower than in rat lung preparations), whereas EH (substrate: benzo[a]pyrene 4,5-oxide) was slightly (about 2-fold) higher in human and GST (substrate: 2,4-dinitrochlorobenzene) had similar activities in both species. Interindividual variations of enzyme activities in human lung were considerable: MO, 40-fold: EH, 5-fold; GST 10-fold. Compared to the control group (non-smokers without cancer) MO activities were slightly but significantly higher in lungs from bronchogenic carcinoma patients whether they were smokers (170% of controls, p < 0.0005) or non-smokers (320% of controls p < 0.025). MO activities of smokers without cancer were only very slightly elevated (140%) of controls, p < 0.05). Specific EH activities compared to the control group were slightly but significantly increased in smokers without cancer (160% of controls, p < 0.0125) and in bronchogenic carcinoma patients whether they used tobacco products (130% of controls, p < 0.005) or not (140% of controls, p < 0.05). Specific GST activities showed no significant differences (p > 0.1) between the various groups studied. The substrate specificity of human lung EH, which was studied using five K-region epoxides of various PAH as substrates, corresponded to that in human and rat liver and in human, mouse and rat skin and to the pure enzyme isolated from rat liver. In contrast to rat liver hepatoma preparations, where EH had been shown to be increased in the tumor tissue and had been identified as a preneoplastic antigen, EH activity in lung microsomal preparations from samples of peripheral squamous cell carcinomas of two subjects had in the tumor tissue only one third of the activity of non-diseased areas of the same lung.
Oesch
F
F
IRL Press Limited, London, UK.
Schmassmann
H
H
Ohnhaus
E
E
Althaus
U
U
Lorenz
J
J
D015660:7-Alkoxycoumarin O-Dealkylase / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002283:Carcinoma, Bronchogenic / Q000201:enzymology*; D002648:Child; D003374:Coumarins / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007206:Individuality; D008168:Lung / Q000201:enzymology*; D008175:Lung Neoplasms / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D012907:Smoking / Q000378:metabolism
D003374:Coumarins; C017299:7-ethoxycoumarin; D015660:7-Alkoxycoumarin O-Dealkylase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases