Uptake and distribution of N-acetylcysteine in mice: tissue-specific effects on glutathione concentrations.
Modulation of cellular thiols has been used to ameliorate the toxic side 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-acetylcysteine (NAC), a cytoprotective drug with multiple therapeutic applications, including use as an adjunct to cancer chemotherapy. Tissue-specific protective effects have previously been observed when NAC has been used in conjunction with chemotherapeutic alkylating agents, but the basis for this was unknown. In view of the contrasting cytoprotective 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 14C-labelled NAC. Radiolabelled NAC was taken up by the majority of tissues at varying rates and levels, except for the brain and spinal cord. The bladder, bone marrow and liver all took up the drug or its metabolites within 15 min of injection. NAC was not found to alter GSH concentrations in the liver, but increased GSH levels in the bladder approximately 2-fold. In contrast, the GSH content of bone marrow was found to decrease by 70-50% after NAC administration. When separate bone marrow cell populations were examined the decrease in GSH was associated with granulocytes, as opposed to lymphocytes, whose GSH levels remained unchanged. These findings provide a possible explanation for the differential cytoprotective effects of NAC.
McLellan
L I
LI
Biomedical Research Centre, University of Dundee, Ninewells Hospital, UK.
Lewis
A D
AD
Hall
D J
DJ
Ansell
J D
JD
Wolf
C R
CR
D000111:Acetylcysteine / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells; D002250:Carbon Radioisotopes; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D014018:Tissue Distribution; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism
D002250:Carbon Radioisotopes; D005978:Glutathione; D000111:Acetylcysteine