Mechanism of enhanced toxicity of 6-mercaptopurine with endotoxin

The enhanced toxicity of 6-mercaptopurine with endotoxin has been confirmed with BALB/c male mice. Striking increases in thioinosinic acid were seen in mice pretreated with endotoxin before injection of 6-mercaptopurine, and were in agreement with the time course of the inhibiting effect of endotoxin on sleeping time. However, there were no significant differences in hypoxanthineguanine phosphoribosyltransferase between control mice and endotoxin-treated mice. Furthermore, there were significant increases in xanthine oxidase after treatment with endotoxin. It is clear that metabolism of 6-mercaptopurine might be modified by activity of the drug-metabolizing enzyme in mouse liver. Based on the effect of endoxotin on 6-mercaptopurine metabolism and the enzymes responsible for 6-mercaptopurine, it is suggested that death caused by 6-mercaptopurine-endotoxin combinations is due to an enhancement of the lethal effect of 6-mercaptopurine. Simultaneous administration of 6-mercaptopurine and endotoxin resulted in a parallel potentiation of either 6-mercaptopurine toxicity or endotoxin toxicity. This interaction was abolished in mice made resistant to the effects of endotoxin. Based on time of death, it is suggested that death caused by 6-mercaptopurineendotoxin combinations is due to an enhancement of the lethal effect of endotoxin. These results indicate that the underlying mechanism of the interaction may involve a dualistic enhancement of each agent.