Differential cytotoxic effects of mizoribine and its aglycone on human and murine cells and on normal and enzyme-deficient human cells.
The growth inhibitory mechanisms of mizoribine, an immunosuppressive imidazole nucleoside used clinically to inhibit rejection reactions after renal transplantation and in the treatment of systemic lupus erythematosus and rheumatoid arthritis, were studied in human and murine cells. We found that (a) human cells were 20- to 60-fold more resistant than murine cells to both mizoribine and its aglycone, (b) adenine phosphoribosyltransferase (APRT)-deficient human cells were resistant to aglycone but not to mizoribine, (c) hypoxanthine phosphoribosyltransferase (HPRT)-deficient human cells were at least 100-fold more sensitive to both mizoribine and aglycone, and (d) the decrease in intracellular GTP broadly paralleled the cytotoxicity in each case. Therefore, data obtained from studies using non-human tissues should be interpreted carefully before clinical application. Results indicate that the growth inhibitory effect of the aglycone but not of mizoribine is mediated by APRT, and depletion of guanine nucleotides is responsible for the effects of both drugs. Our data also suggest that the drugs may reduce mutant HPRT-deficient somatic cells in vivo, and may cause enhanced adverse reactions in HPRT-deficient individuals. The drug may have altered effects in patients receiving other purine or pyrimidine analogs.
Terai
C
C
Institute of Rheumatology, Tokyo Women's Medical College, Japan.
Hakoda
M
M
Yamanaka
H
H
Kamatani
N
N
Kashiwazaki
S
S
D000228:Adenine Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed / Q000201:enzymology; D002478:Cells, Cultured / Q000201:enzymology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000172:deficiency* / Q000235:genetics; D007166:Immunosuppressive Agents / Q000633:toxicity*; D051379:Mice; D009154:Mutation; D012263:Ribonucleosides / Q000633:toxicity*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D000228:Adenine Phosphoribosyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase