Chemopreventive properties and mechanisms of N ‐acetylcysteine. The experimental background

The thiol N ‐acetylcysteine (NAC), now under clinical trial for cancer chemoprevention both in Europe (project Euroscan) and in the US (National Cancer Institue), has been shown during the past decade to exert protective effects in a variety of experimental test systems. NAC inhibited spontaneous mutagenicity and that induced by a number of chemical compounds and complex mixtures. Moreover, NAC significantly decreased the incidence of neoplastic and preneoplastic lesions induced by several chemical carcinogens in rodents (mice, rats, hamsters), e.g. , in lung, trachea, colon, liver, mammary gland, Zymbal gland, bladder and skin. Our studies provided evidence that multiple mechanisms contribute to NAC antimutagenicity and anticarcinogenicity. They include extracellular mechanisms, such as detoxification of reactive compounds due to the nucleophilic and antioxidant properties of NAC, inhibition of nitrosation products, and enhancement of thiol concentration in intestinal bacteria; trapping and enhanced detoxification of carciongens in long‐lived non‐target cells, such as erythrocytes and bronchoalveolar lavage cells; mechanisms working in the cytoplasm of target cells, such as replenishment of GSH stores, modulation of metabolism of mutagens/carcinogens, blocking of electrophiles, and scavenging of reactive oxygen species; and nuclear effects, such as inhibition of DNA adduction by metabolites of carcinogens, inhibition of “spontaneous” mutations, attenuation of carcinogen‐induced DNA damage, and protection of nuclear enzymes, such as poly(ADP‐ribose) polymerase. In particular, benzo(a)pyrene diolepoxide‐DNA adducts in rats exposed either to benzo(a)pyrene or cigarette smoke were prevented by NAC not only in target organs for carcinogenicity, such as lung and trachea, but also in other organs, such as heart, aorta and testis, where these molecular biomarkers have been tentatively associated with cardiomyopathies, atherosclerosis and hereditary diseases, respectively. The protective mechanisms of NAC are expected to affect not only initiation but also promotion and progression, due to the reiterate involvement of certain key mechanisms in carcinogenesis. Moreover, recent studies demonstrate that NAC can also affect the steps of invasion and metastasis, including the specific inhibition of type IV collagenases degrading basement membranes, inhibition of chemotactic and invasive activities of human and murine malignant cells, delay of primary tumor formation in mice, and inhibition of lung metastases. Evidence was also provided that administration of pharmacological doses of NAC sharply decreases urinary excretion of mutagens in smokers.