Azathioprine lymphocytotoxicity. Potentially lethal damage by its imidazole derivatives.

The immunosuppressive agent 6-(1-methyl-4-nitroimidazole-5-yl)-thiopurine (azathioprine, AZA) is metabolized to the purine antagonist 6-mercaptopurine (6-MP) and to 5-substituted 1-methyl-4-nitro-5-thioimidazoles or- aminoimidazoles. Besides the cytostatic (growth inhibition) and cytocidal (cell killing) effect of the anti-metabolite 6-MP, which can be antagonized by exogenous purine supplementation, AZA has an additional effect, which cannot be antagonized by purines. This effect is due to electron-affine imidazole derivatives, which are generated by a nucleophilic attack on the AZA molecule. A synthetic imidazole derivative (1-methyl-4-nitro-5-chloro-imidazole, MNCI) develops cytostatic and cytocidal effects in two different permanent human lymphoblastoid cultures (LS2 and CH4) with threshold concentrations of 8 x 10(-5) and 6 x 10(-5) mol/l, respectively. This imidazole derivative with the nitro- and chloro-group in ortho-position seems to be more reactive than other imidazole derivatives. It interferes with the redox potential of the cells. It causes glutathione depletion and sublethal conditioning of the cells (reduced repair capacity = potentially lethal damage = PLD = chemosensitization). The immunosuppressive action of AZA depends on the synergistic cooperation of the relatively weak cytostatic effect of low doses of 6-MP and the chemosensitizing effect of PLD which is induced by highly reactive imidazole derivatives.