METABOLIC ALTERATIONS PRODUCED BY CIGARETTE-SMOKE IN RAT LUNG AND LIVER, AND THEIR MODULATION BY ORAL N-ACETYLCYSTEINE

Male Sprague-Dawley rats were exposed whole-body to the mainstream smoke produced by a commercial filter cigarette for 8 consecutive days, accounting for a cumulative exposure to the smoke of 75 cigarettes. Liver and lung S12 fractions were used in the Salmonella mutagenicity test in order to assess either the decrease of potency of a direct-acting mutagen (sodium dichromate) or the metabolic activation of promutagens, including cigarette smoke itself and its condensate, benzo[a]pyrene and its 7,8-diol, the aromatic amine 2-aminofluorene, and the heterocyclic amine 3-amino-1-methyl-5H-pyrido(4,3)indole. Morover, individual biochemical parameters were measured in the liver and lung of the same rats and, in the case of cytochrome P-450-dependent mono-oxygenases, also in the heart of untreated or Aroclor-treated rats. The monitored biochemical parameters included aryl hydrocarbon (benzo[a]pyrene) hydroxylase and ethoxyresorufin deethylase in microsomal fractions, epoxide (benzo[a] pyrene-4,5-oxide) hydrolase in both microsomal and cytosolic fractions, glutathione (GSH) and GSH S-transferase in the cytosol. Exposure to cigarette smoke resulted in a number of significant metabolic changes, as compared to sham-exposed rats. The most pronounced alterations consisted in a 2.6-fold induction of aryl hydrocarbon hydroxylase in the lung and 8-fold induction of ethoxyresorufin deethylase in the liver, and in a marked stimulation of the liver metabolic activation of all promutagens. The last effect was inhibited by the oral administration of the chemopreventive agent N-acetylcysteine. On the whole, there was a poor correlation between the monitored biochemical and mutagenicity end-points. Moreover, metabolic data did not substantially account for the massive damage produced by cigarette smoke and the striking protective effects exerted by N-acetylcysteine, which were established in parallel studies evaluating histopathological, cytogenetic, and molecular dosimetry end-points in specimens of the same animals.