mercaptopurine and Ascites

Thiopurines play a pivotal role in the management of inflammatory bowel disease. Azathioprine and mercaptopurine have been associated with a number of liver abnormalities, including hepatitis, veno-occlusive disease, nodular regenerative hyperplasia, and peliosis hepatitis. Patients treated with azathioprine and mercaptopurine have their liver chemistry tests routinely checked due to this potential for hepatotoxicity. Hepatoportal sclerosis is a cause of non-cirrhotic portal hypertension that is increasingly being recognized; its etiopathogenesis is not well defined. We present the first case report of mercaptopurine-induced hepatoportal sclerosis leading to non-cirrhotic portal hypertension in a patient with Crohn's disease. He had been treated with mercaptopurine for five years, and his liver chemistry tests were always within normal limits. This case underscores the potential serious liver adverse events that may arise silently and go undetected during treatment with mercaptopurine, and should alert clinicians as to the potential need to discontinue mercaptopurine in this setting.

Topics: Ascites; Crohn Disease; Humans; Hypertension, Portal; Immunosuppressive Agents; Intestinal Obstruction; Liver Function Tests; Male; Mercaptopurine; Portal System; Sclerosis; Young Adult

Topics: Alkylating Agents; Animals; Antibiotics, Antineoplastic; Ascites; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Drug Resistance; Leukemia L1210; Leukemia, Experimental; Mercaptopurine; Methotrexate; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Piperazines; Piperidines; Transplantation, Homologous

Topics: Animals; Ascites; Body Weight; Carcinoma; Carcinoma 256, Walker; Coenzymes; Female; Half-Life; Liver; Lung; Male; Mercaptopurine; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Sarcoma; Spleen; Time Factors; Transplantation, Homologous

Topics: Adenocarcinoma; Amides; Animals; Antineoplastic Agents; Ascites; Female; Formates; Guinea Pigs; Injections, Intraperitoneal; Leukemia L1210; Leukemia, Experimental; Male; Mercaptopurine; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Nucleosides; Sarcoma, Experimental; Transplantation, Homologous

Topics: Agar; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Ascites; Carcinoma, Hepatocellular; Clone Cells; Culture Techniques; Diffusion; Liver Neoplasms; Mercaptopurine; Methods; Mitomycins; Neoplasms, Experimental; Nitrogen Mustard Compounds; Rats; Thiotepa

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Ascites; Carcinoma, Hepatocellular; Cobalt Isotopes; Colchicine; Cyclophosphamide; Dactinomycin; Female; Glycogen; Liver Neoplasms; Mechlorethamine; Mercaptopurine; Mitomycins; Neoplasm Transplantation; Neoplasms, Experimental; Oligosaccharides; Rats; Sarcoma, Yoshida

Topics: Animals; Antineoplastic Agents; Ascites; Carcinoma, Ehrlich Tumor; Cyclophosphamide; Electronics, Medical; Mannomustine; Melphalan; Mercaptopurine; Methods; Mice; Sarcoma 180

1. The formation of adenosine 5'-phosphate, guanosine 5'-phosphate and inosine 5'-phosphate from [8-(14)C]adenine, [8-(14)C]guanine and [8-(14)C]hypoxanthine respectively in the presence of 5-phosphoribosyl pyrophosphate and an extract from Ehrlich ascites-tumour cells was assayed by a method involving liquid-scintillation counting of the radioactive nucleotides on diethylaminoethylcellulose paper. The results obtained with guanine were confirmed by a spectrophotometric assay which was also used to assay the conversion of 6-mercaptopurine and 5-phosphoribosyl pyrophosphate into 6-thioinosine 5'-phosphate in the presence of 6-mercaptopurine phosphoribosyltransferase from these cells. 2. At pH 7.8 and 25 degrees the Michaelis constants for adenine, guanine and hypoxanthine were 0.9 mum, 2.9 mum and 11.0 mum in the assay with radioactive purines; the Michaelis constant for guanine in the spectrophotometric assay was 2.6 mum. At pH 7.9 the Michaelis constant for 6-mercaptopurine was 10.9 mum. 3. 25 mum-6-Mercaptopurine did not inhibit adenine phosphoribosyltransferase. 6-Mercaptopurine is a competitive inhibitor of guanine phosphoribosyltransferase (K(i) 4.7 mum) and hypoxanthine phosphoribosyltransferase (K(i) 8.3 mum). Hypoxanthine is a competitive inhibitor of guanine phosphoribosyltransferase (K(i) 3.4 mum). 4. Differences in kinetic parameters and in the distribution of phosphoribosyltransferase activities after electrophoresis in starch gel indicate that different enzymes are involved in the conversion of adenine, guanine and hypoxanthine into their nucleotides. 5. From the low values of K(i) for 6-mercaptopurine, and from published evidence that ascites-tumour cells require supplies of purines from the host tissues, it is likely that inhibition of hypoxanthine and guanine phosphoribosyltransferases by free 6-mercaptopurine is involved in the biological activity of this drug.

Topics: Adenine; Adenine Nucleotides; Adenosine Monophosphate; Animals; Ascites; Carcinoma, Ehrlich Tumor; Diphosphates; Electrophoresis; Enzyme Inhibitors; Glucosyltransferases; Guanine; Guanine Nucleotides; Hypoxanthines; Kinetics; Mercaptopurine; Nucleotides; Pharmacology; Purines; Research; Spectrophotometry; Transferases; Xanthines

1. A strain of Ehrlich ascites-tumour cells that showed little inhibition of growth in the presence of 6-mercaptopurine accumulated less than 5% as much 6-thioinosine 5'-phosphate in vivo, in the presence of 6-mercaptopurine, as did the sensitive strain from which it was derived. 2. Specific activities of the phosphoribosyltransferases that convert adenine, guanine, hypoxanthine and 6-mercaptopurine into AMP, GMP, IMP and 6-thioinosine 5'-phosphate were similar in extracts of the resistant and the sensitive cells. 3. As found previously with sensitive cells, 6-mercaptopurine is a competitive inhibitor of guanine phosphoribosyltransferase and hypoxanthine phosphoribosyltransferase from the resistant cells and does not inhibit the adenine phosphoribosyltransferase from these cells. Michaelis constants and inhibitor constants of the purine phosphoribosyltransferases from resistant cells did not differ significantly from those measured with the corresponding enzymes from sensitive cells. 4. Resistance to 6-mercaptopurine in this case is probably not due to qualitative or quantitative changes in these transferases.

Topics: Adenine; Adenine Nucleotides; Animals; Ascites; Carcinoma, Ehrlich Tumor; Chromatography; Electrophoresis; Enzyme Inhibitors; Glucosyltransferases; Guanine; Guanine Nucleotides; Humans; Hypoxanthines; Ion Exchange Resins; Kinetics; Mercaptopurine; Metabolism; Nucleotides; Pentosyltransferases; Pharmacology; Research; Xanthines

Topics: Animals; Ascites; Carcinoma; Carcinoma, Ehrlich Tumor; Lactates; Mercaptopurine; Metabolism; Nucleosides; Research; Thioinosine

Topics: Adenine Nucleotides; Animals; Ascites; Azaserine; Carcinoma; Carcinoma, Ehrlich Tumor; Chromatography; Histocytochemistry; Mercaptopurine; Metabolism; Mice; Neoplasms, Experimental; Nucleotides; Pharmacology; Phosphoric Monoester Hydrolases; Research

Topics: 5'-Nucleotidase; Animals; Ascites; Carcinoma; Carcinoma, Ehrlich Tumor; Mercaptopurine; Nucleotidases

Topics: Animals; Antineoplastic Agents; Ascites; Busulfan; Chemical Phenomena; Chemistry; In Vitro Techniques; Mercaptopurine; Neoplasms; Nitrogen Mustard Compounds; Pharmacology; Sarcoma; Sarcoma, Yoshida

Topics: Ascites; Biochemical Phenomena; Carcinoma; Humans; Mercaptopurine; Neoplasms; Nucleosides; Nucleotides

Topics: Ascites; Biochemical Phenomena; Carcinoma; Mercaptopurine; Neoplasms; Nucleosides; Nucleotides

Topics: Animals; Antineoplastic Agents; Ascites; Azaserine; Carcinoma, Ehrlich Tumor; Humans; Mercaptopurine; Neoplasms, Experimental; Pyrimidines; Thioguanine

Topics: Animals; Antineoplastic Agents; Ascites; Carcinoma, Ehrlich Tumor; Humans; Mercaptopurine; Purines; Sulfhydryl Compounds

Topics: Animals; Ascites; Azaserine; Azoles; Carcinoma, Ehrlich Tumor; Humans; Mercaptopurine; Neoplasms; Neoplasms, Experimental; Pyrimidines; Serine; Thioguanine

Topics: Animals; Ascites; Carcinoma; Mercaptopurine; Neoplasms, Experimental

Topics: Antimetabolites; Ascites; Carcinoma; Mercaptopurine; Neoplasms; Nucleosides; Nucleotides; Purine Nucleosides

Topics: Antimetabolites; Ascites; Carcinoma; Humans; Mercaptopurine; Neoplasms; Physiological Phenomena

Topics: Animals; Ascites; Carcinoma, Ehrlich Tumor; Mercaptopurine; Neoplasms; Phosphates

Topics: Animals; Antineoplastic Agents; Ascites; Azaserine; Cell Cycle; Cell Proliferation; Mercaptopurine; Neoplasms, Experimental; Serine; Thioguanine

Topics: Animals; Ascites; Humans; Mercaptopurine; Neoplasms, Experimental; Thioguanine

Topics: Animals; Anti-Bacterial Agents; Ascites; Azaserine; Carcinoma, Ehrlich Tumor; Mercaptopurine; Neoplasms; Purines