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Sprague-Dawley rats given azathioprine (AZP) and phenobarbital in the diet and drinking water, respectively, for 3 to 4 weeks developed severe liver damage. Elevations of serum alkaline phosphatase and γ-glutamyl transpeptidase activities were associated with increased hepatic glucose 6-phosphate dehydrogenase levels and decreased liver glucose 6-phosphatase activities. Light and electron microscopic observations revealed centrolobular necrosis with large scars and the proliferation of the mitochondria and rough endoplasmic reticulum. Similar biochemical and morphological observations were also obtained by feeding the diets containing AZP or its metabolites such as 6-mercaptopurine (6-MP) and 6-thioinosine ribose (TIR) alone. Injections of reduced glutathione (GSH) during the feeding of AZP-containing diet did not prevent but rather deteriorated AZP-induced liver injury. An increase of hepatotoxicity by simultaneous injections of GSH could be similarly obtained in acute liver injury following a single administration of AZP. Furthermore, an inhibitor of xanthine oxidase which catalizes the breakdown of 6-MP, 4-hydroxypyrazole (3, 4-)pyrimidine, resulted in the severity of AZP- and especially 6-MP-induced acute liver injury.These results suggest that AZP-induced hepatotoxicity may be due to the inhibition of nucleic acid and protein biosyntheses by active metabolites such as 6-thioinosine monophosphate, which are formed from AZP via 6-MP and TIR.
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