Demonstration of enzymatic activity converting azathioprine to 6-mercaptopurine

The enzymatic conversion of azathioprine to 6-mercaptopurine was detected at pH 6.5 with rat liver supernatants, although the non-enzymatic reaction predominated at pH 7.0 and 7.5. Glutathione S-transferase may catalize this conversion. Activities of the enzyme in liver with both zathioprine and 1,2-dichloro-4-nitrobenzene as substrate decreased upon carbon tetrachloride-induced hepatic injury. These results may explain an ineffectiveness of azathioprine in patients with severe hepatic damage.</p

Decreased Disappearance Rate of 1-(2-Tetrahydrofuryl)-5-Fluorouracil (FT-207) from the Blood and its Unresponsiveness to Tocopheryl Nicotinate and Indomethacin in Patients with Primary Hepatocellular Carcinoma

The disappearance rates(K) of FT-207 from the blood in patients with primary hepatoma and advanced cirrhosis of the liver were significantly lower than those in control patients with cancer but normal liver function. Pretreatment with tocopheryl nicotinate and indomethacin increased the K values in the control subjects, but was without effect on the K values in patients with primary hepatoma.</p

Biochemical and morphological study on hepatotoxicity of azathioprine in rat.

Sprague-Dawley rats given azathioprine in the diet for 3 to 4 weeks developed severe liver damage. Elevations of serum alkaline phosphatase and gamma-glutamyl transpeptidase activities were associated with increased hepatic glucose 6-phosphate dehydrogenase levels and decreased liver glucose 6-phosphatase activities, i.e., conditions which were commonly observed in various hepatotoxin-induced liver injuries. Light and electron microscopic observations revealed centrolobular necrosis with large scars and the proliferation of the mitochondria and rough endoplasmic reticulum. This model could be used to study the mechanisms of azathioprine-induced liver damage and its prevention.</p

Increased disappearance rate of 1-(2-tetrahydrofuryl)-5-fluorouracil in reduced glutathione- or vitamin E-treated rats and its unresponsiveness to these drugs in carbon tetrachloride-injured rats

The pharmacokinetics of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT) were analysed by measuring its disappearance rate (K) from the circulating blood using a high-pressure liquid chromatographic technique. An increase in the disappearance rate of FT was observed by treatment with reduced glutathione (GSH)- or tocopheryl nicotinate-treated rats. The clearance rates of FT from the circulating blood in carbon tetrachloride (CCl(4))-injured rats were much smaller than those in untreated rats. The unresponsiveness of K values to treatment with GSH or tocopheryl nicotinate was seen in liver-injured rats

Nephrotoxicity of Pyrroloquinoline Quinone in Rats

When pyrroloquinoline quinone (PQQ) was intraperitoneally injected into rats daily for 4 days at a dose of 11.5 mg/kg body weight/injection, functional and morphologic changes of the kidneys were clearly observed. The most prominent finding was necrotic and degenerative changes of the proximal tubular epithelium as well as hematuria and an elevation of serum creatinine concentration