Monooxygenase, epoxide hydrolase, and glutathione-S-transferase activities in human lung. Variation between groups of bronchogenic carcinoma and non-cancer patients and interindividual differences

Abstract

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 long. 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-deethylatlon of 7-ethoxycoumarin and only after modification of the assay method. Evidence was obtained for the presence of a diffusible, but not dialyslble, 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 EM (substrate: benzo 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 nonsmokers (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 (13076 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 EM, 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 ret liver hepatoma preparations, where EHI 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 nondiseased areas of the same lung.

Longitudinal Study of Urinary Phenanthrene Metabolite Ratios: Effect of Smoking on the Diol Epoxide Pathway

“…1). In addition, some studies indicate that epoxide hydrolase, which is also involved in diol epoxide formation, is induced in smokers, but others show no change (38)(39)(40)(41).…”

Control of Glucose-6-Phosphate Dehydrogenase Deficiency on the Formation of Mutagenic and Carcinogenic Metabolites Derived from Benzo(a)pyrene

“…This enzymatic activity, either stimulated by inducers or not, exhibits great interindividual variations in human tissues (7,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). To minimize such variations only HL hydroxylating 2.5-8.0 pmol of BaP/min/mg protein after induction with BaA, were used.…”

Genetic predisposition to lung cancer

“…Table II summarises four case-control comparisons of AHH activity in lung tissue. One (Oesch et al, 1980) found higher activity in cases (statistically significant for non-smokers but not smokers) but the difference was only about 2-fold and might readily have been produced by bias. The three other controlled studies were negative.…”

“…The Ah locus has been assigned to chromosome 12 in the mouse (Cobb et al, 1987). Its major product is a cytosolic receptor that binds inducing compounds, then migrates to the nucleus (Okey et al, 1980). Increased cytochrome P,-450 mRNA synthesis follows (Israel & Whitlock, 1984).…”

“…Cigarette smoking increases AHH activity in the lung and in tissues distant from the lung -both baseline and induced levels are higher in smokers than non-smokers (Conney, 1982;Cantrell et al, 1973). Other factors associated with cancer that may influence AHH activity include serum cholesterol (Korsgaard & Trell, 1978) and asbestos exposure (Snodgrass et al, 1981), while several dietary factors (which may change with hospital admission) also affect AHH activity (Conney, 1982 (Oesch et al, 1980;Karki et al, 1987); the reason is uncertain.…”