Azathioprine, a genotoxic agent to be considered non-genotoxic in man

Abstract

Azathioprine, an immunosuppressive drug, has been used for 25 years. Azathioprine is rapidly converted into a number of metabolites after absorption. Maximum blood levels in experimental animals (mice) were 11.3 μg/ml after a dosage of 33.3 mg/kg. Generally, levels of less than 1 μg/ml are found. As azathioprine is ineffective in hypoxanthine guanine phosphoribosyltransferase (HPRT)-deficient patients, it will be clear that for immunosuppressive activity azathioprine must be metabolised. Regarding mutagenic activity, its mutagenicity for bacteria seems irrelevant for man because the nitroimidazole moiety can be reduced by bacteria but not or hardly at all by mammalian tissues. So 6-mercaptopurine (a metabolite of azathioprine) and its metabolites should be regarded as the active compounds. In vitro azathioprine can induce chromosome aberrations and other cytogenetic events at high, non-physiological doses. However, in view of the low blood levels it is unlikely that azathioprine can induce chromosome aberrations in kidney transplant patients. It is more probable that azathioprine inhibits the elimination of such aberrant cells through its immunosuppressive activity. It should be pointed out that in microbial mutagenicity systems also, azathioprine concentrations that are not reached in patients are needed to obtain an increased mutation rate. Azathioprine can induce tumours in rats at high doses and in immunocompromised mice at lower doses. In healthy mice most carcinogenic experiments were negative. Regarding carcinogenesis in man it should be pointed out that in some series of kidney transplant patients an increased incidence of tumours occurred within 5 years (a very short period for the induction of carcinomas in man by carcinogenic agents or radiation) and that nearly similar experiences are reported for the non-mutagenic agent cyclosporin. In other series of patients with other diseases (e.g., rheumatoid arthritis) no increased tumour incidence is reported. Even some cases of regression of tumours after azathioprine withdrawal are mentioned in the literature. Azathioprine is known to interfere with the synthesis of some immunological factors (e.g., interleukin-2). Furthermore, azathioprine is teratogenic, probably due to inhibition of protein synthesis. From these facts it can be concluded that although azathioprine has genotoxic properties its use as a drug does not induce genotoxic or carcinogenic events in patients. So the non-genotoxic activities of azathioprine lead to the same result by not eliminating damaged cells that occur spontaneously or are induced by other agents.