CARCINOGENICITY OF AZATHIOPRINE - AN S-AR INVESTIGATION

Besides its use in the treatment of a variety of presumed autoimmune d iseases, azathioprine is given as an immunosuppressant to patients who have had renal transplants. Though epidemiological studies have provi ded ''sufficient'' evidence of its carcinogenicity in humans, the carc inogenicity tests in rats and mice are considered to be inconclusive b ecause of limitations in the design and results of these tests (IARC, 1981, 1987). Rosenkranz and Klopman (1991) used the CASE program to id entify the structural features responsible for its carcinogenicity. Th ey concluded that this genotoxic chemical was a carcinogen due to the presence of the molecular fragment C''-S-C =. The finding was based on the presence of this biophore fragment in five other compounds, namel y: 2-amino-5-nitrothiazole, 2-mercaptobenzothiazole, fenthione, 4,4'-t hiodianiline and nithiazide. Recently, Ashby (1992) has expressed conc ern over the validity of their findings. With the aim of contributing to this debate on the mechanism of carcinogenicity of azathioprine, we have analyzed the structural basis of carcinogenicity of azathioprine and the five support compounds using the carcinogenicity predictor of our toxicity prediction program, TOPKAT. The results. more in line wi th Ashby's concerns, indicate that no molecular fragment involving the S atom is associated with the carcinogenic properties of these molecu les. According to the TOPKAT program the carcinogenicity, if any, of a zathioprine is due to the NO2 electrophile because its other major str uctural features are found to be either associated with non-carcinogen icity or do not discriminate carcinogens from non-carcinogens.