Inter-individual differences in oxidative benzo(a)pyrene metabolism by normal and tumorous surgical lung specimens from 105 lung cancer patients.

Abstract

AbstractOxidative benzo(a)pyrene (BP) metabolism was studied in 12,000 g(S12) supernatant fractions of surgical lung specimens obtained from lung cancer patients undergoing surgical resection. Arylhydrocarbon (BP)hydroxylase (AHH) activity was determined in both normal and tumorous lung tissue specimens from the same patient. A more than 20‐fold inter‐individual variation in AHH activity was found in both the normal and the tumorous lung tissue samples investigated. The apparent KM of the pulmonary enzyme (1–2.5 × 10−4 M) was identical in tumorous and normal tissue. High‐performance liquid chromatography (HPLC) of ethyl acetate‐extractable BP metabolites from the normal lung tissue of six patients identified phenols, dihydrodiols and quinones of BP. The mean yields of these metabolites were very similar to those obtained in assays in the presence of lung S12 from BDVI rats, except that more trans−9, 10‐dihydro‐9, 10‐dihydroxy‐BP (BP‐9, 10‐diol) was formed in the presence of human lung S12. The formation of 3‐hydroxy‐BP (3‐HO‐BP) and BP‐9, 10‐diol in human lung specimens, however showed variations up to 7‐ and 13‐fold, respectively. In normal lung specimens, the total amounts of 3‐HO‐BP and 9‐HO‐BP formed correlated positively with the total amounts of trans‐7, 8‐dihydro‐7, 8‐dihydroxy‐BP (BP‐7, 8‐diol), BP‐9, 10‐diol and trans‐4, 5‐dihydro‐4, 5‐dihydroxy‐BP (BP‐4, 5‐diol) formed (r = 0.83; p < 0.05). A positive correlation was also found between the AHH activity in normal and tumorous tissue from all cancer patients (r = 0.24; p < 0.05). The ratio (R) of AHH activity in tumorous tissue to that in normal tissue from the same lung cancer patient was < 1 in 73 patients, 1 in 2 patients, and > 1 in 11. In 7 of 10 subjects who underwent surgical resection for suspected lung tumours, but in whom histological analysis revealed no malignant tissue, R was > 1 for the AHH activity in the inflammatory tissue to that in normal tissue. The observation of consistently lower AHH activity in malignant lung tissue parallels findings in hyperplastic liver nodules induced in rats by hepatocarcinogens. The frequency distribution of pulmonary AHH activity in normal and tumorous tissue from 105 lung cancer patients, with all types of tumours, was compatible with a unimodal distribution of the enzyme activity. In a subset of 43 patients with squamous‐cell carcinoma, the same distribution was seen; in those patients, AHH activity in tumorous tissue correlated negatively (r = −0.18; p > 0.10) with the number of cigarettes smoked per day prior to surgery. No differences were observed between the mean values for AHH activity in cases of squamous‐cell carcinoma and those of adenocarcinoma. No relationship was found between AHH activity in normal or tumour tissue and the age of patients. Whether differences in pulmonary AHH activity represent a host risk factor in persons who smoke remains to be investigated.