Organospecific activation of azathioprine in mice: role of liver metabolism in mutation induction

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Abstract
The organ-specific mutagenicity of azathioprine was examined by means of the intrasangulneous host-mediated assay in mice, combined with the D7 strain of Saccharomyces cerevisiae To assay for changes in the frequency of mitotic gene conversion, mitotic crossing-over and point reverse mutation frequency, a single i.p. dose of azathioprine was administered. Kidney-mediated mutagenicity was significantly enhanced. The ability of liver, kidney and lung S9 fractions (from Na-phenobarbital + β-naphthoflavone induced mice) to activate azathioprine into genotoxic intermediates was also evaluated in vitro by incubating organ homogenates with S.cerevisiae cells as a target organism. Organ-specific activation was demonstrated only in the liver. The relative role of liver metabolism in the induction of mutations and tumor induction was investigated in in vivo experiments with partially hepatectomized mice. The data demonstrated that liver affects both kidney- and lung-mediated mutagenicity and indicated that hepatic metabolism can contribute mutagenic metabolites for cancer initiation by azathioprine.