Metabolism of 6-thiopurines. I. Irreversible binding of a metabolite of 6-thiopurine to mammalian hepatic protein in vitro.

Irreversible binding of a metabolite of 6-thiopurine to mammalian hepatic protein was demonstrated in vitro. Protein binding occurred with rat, hamster, rabbit, pig and human liver microsomes in the presence of NADPH and oxygen. The involvement of the cytochrome P-450 system in the activation of 6-thiopurine to the chemically reactive metabolite was supported by the effects of inhibitors of cytochrome P-450 mediated reactions and phenobarbital induction. The binding of the metabolite appeared to be through formation of a mixed disulfide between 6-thiopurine and protein thiols. In the presence of thiols such as glutathione, the irreversible protein binding of 6-thiopurine was inhibited. No significant binding of 6-thiopurine to other tissues was observed in vitro with rats.