Pulmonary Metabolism of Mutagens and Its Relationship with Lung Cancer and Smoking Habits1

The S-12 fractions of lung peripheral parenchyma obtained from 80 male individuals, aged 17-71 years, were assayed as blind samples for the ability either to convert promutagens into bacterial mutagens or to decrease the potency of direct-acting mutagens in the Ames reversion test. In this system, lung preparations were completely ineffective in activating an .V-niimsn compound (i.e., \-nitrosoniorpholinr) and polycyclic aromatic hydrocarbons {i.e., 3-methylcholanthrene and benzo(a)pyrene| or their metabolites (/.<•., 3-hydroxy-benzo(a)pyrene and benzo(fl)pyrene-frfl/w-7,8-diol|. They yielded a borderline and sporadic activation of a cigarette smoke condensate, and a weak but frequent activation of an aromatic amine (i.e., 2-aminofluorene), of a heterocyclic amine (i.e., 2-amino-3,4-dimethylimidazo|4,S-/|quinoline) and of a diamide (i.e., cyclophosphamide). The pulmonary metabolism was more ori ented in the sense of detoxification, as shown by the consistent decrease of potency of direct-acting mutagens, including a metal (i.e., sodium dichromate), an acridine and nitrogen mustard derivative (i.e., 2-methoxy6-chloro-9-|3-(2-chloroniethyl)aminopropylaminoJacridine or ICR 191), an epoxide (i.e., epichlorohydrin) and an jY-oxide (i.e., 4-nitroquinoline/V-oxide). As assessed by means of a numerical score quantifying the variation of mutagenicity, a marked interindividual variability (up to 20fold) was detected in the ability of lung specimens to affect the mutagen icity of test compounds. Such variability was not significantly related to the protein concentration of S-12 fractions, nor to the age of the patients under scrutiny, who during hospitalization were on normal institutional diets and did not receive any special drug treatment. The only significant difference between 20 noncancer and 60 lung cancer patients, irrespective of the histolÃ3gica!type, was a decreased activation of cyclophosphamide in the latter group. Probably due to the high prevalence of smokers among lung cancer patients, a significantly decreased activation of cyclo phosphamide was also observed in the group of smokers. Smoking habits were associated with a stimulation of detoxifying mechanisms which, in agreement with the results of a previous study with human alveolar macrophages (F. L. Petrilli et al., J. Clin. Invest., 77:1917-1924,1986), was significant in the case of sodium dichromate. Such effect was further enhanced by considering only individuals smoking during the last 24 h before collecting lung specimens, and under these conditions it became significant also for ICR 191. In any case, the bulk of the interindividual variations could not be explained by the analyzed sources of variability.