UPTAKE AND DISTRIBUTION OF N-ACETYLCYSTEINE IN MICE - TISSUE-SPECIFICEFFECTS ON GLUTATHIONE CONCENTRATIONS

Modulation of cellular thiols has been used to ameliorate the toxic si de effects associated with cancer chemotherapy and is currently being investigated as a novel therapeutic strategy in cancer treatment. One of the most extensively studied modulators of thiol levels is N-acetyl cysteine (NAC), a cytoprotective drug with multiple therapeutic applic ations, including use as an adjunct to cancer chemotherapy. Tissue-spe cific protective effects have previously been observed when NAC has be en used in conjunction with chemotherapeutic alkylating agents, but th e basis for this was unknown. In view of the contrasting cytoprotectiv e effects of NAC in bladder and bone marrow we examined the effect of this compound on mouse liver, bladder and bone marrow glutathione (GSH ) levels, as well as the disposition of C-14-labelled NAC. Radiolabell ed NAC was taken up by the majority of tissues at varying rates and le vels, except for the brain and spinal cord. The bladder, bone marrow a nd liver all took up the drug or its metabolites within 15 min of inje ction, NAC was not found to alter GSH concentrations in the liver, but increased GSH levels in the bladder similar to 2-fold. In contrast, t he GSH content of bone marrow was found to decrease by 70-50% after NA C administration. When separate bone marrow cell populations were exam ined the decrease in GSH was associated with granulocytes, as opposed to lymphocytes, whose GSH levels remained unchanged. These findings pr ovide a possible explanation for the differential cytoprotective effec ts of NAC.