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Enzymes of Uracil Catabolism in Normal and Neoplastic Human Tissues1 / Fardos N

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Enzymes of Uracil Catabolism in Normal and Neoplastic Human Tissues1 / Fardos N [CANCER RESEARCH 45, 5405-5412, November 1985] Enzymes of Uracil Catabolism in Normal and Neoplastic Human Tissues1 / Fardos N. M. Naguib,2 Mahmoud H. el Kouni, and Sungman Cha Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912 ABSTRACT to homogeneity from rat liver cytosol (9). Dihydropyrimidinase (5,6-dihydropyrimidine amidohydrolase, Enzymes of the pyrimidine base catabolism, dihydrouracil de- EC 3.5.2.2) is the second enzyme of pyrimidine base degrada hydrogenase (EC 1.3.1.2), dihydropyrimidinase (EC 3.5.2.2), and tion. It is responsible for the reversible hydrolytic ring opening of /3-ureidopropionase (EC 3.5.1.6) were compared in the cytosolic dihydrouracil and dihydrothymine and is located in the cytosol extract of several normal and neoplastic human tissues. The fraction (12-15). activity was measured by following the catabolism of [6-14C]- /3-Ureidopropionase (A/-carbamoyl-j8-alanine amidohydrolase, uracil to dihydrouracil, carbamyl-/3-alanine, and /3-alanine. Sub EC 3.5.1.6) is the last of the pyrimidine degradative enzymes. It strate inhibition, hysteresis, allosterism, and the lack of dihydro splits the /3-ureidopropionic acid (carbamyl-ß-alanine) or /3-urei- pyrimidinase are pointed out as special problems in assaying doisobutyric acid formed by dihydropyrimidinase from dihydrour enzymes of pyrimidine degradation. The activity of dihydrouracil acil or dihydrothymine into 0-alanine or /9-aminoisobutyric acid, dehydrogenase has been demonstrated in several human extra- ammonia, and carbon dioxide (Chart 1). /3-Ureidopropionase is hepatic tissues and tumors. The enzyme is rate limiting in extra- also located in the cytosol (14, 16, 17). The reaction catalyzed hepatic solid tumors but not in their normal counterparts. Some by this enzyme is irreversible. of these solid tumors contain greater amounts of activity than Reports on dihydrouracil dehydrogenase activity in the various do their normal equivalents, which encourages the use of inhibi extrahepatic tissues are contradictory. The kidney was reported tors of this enzyme in conjunction with treatment of these tumors to be the only extrahepatic tissue to contain dihydrouracil dehy by 5-f luorouracil. Because of the lack of a pattern in dihydrouracil drogenase (4,18-20). However, this activity was later reported dehydrogenase activity between tumors and normal tissues, the to be present in rat thymus, intestinal mucosa, spleen, kidney, enzyme is not a good marker for tumorigenicity. Dihydropyrimi brain cortex, skeletal muscles, heart, lung, stomach, and bone dinase, on the other hand, is highly active in all solid tumors marrow (21,22); in mouse colon and colon tumors (23); in human studied but not in their normal counterparts; therefore, we sug kidney and kidney tumors (24); and in normal and neoplastic gest that dihydropyrimidinase can serve as a good marker of human colon, lung, and stomach (25). The early discrepancies in tumorigenicity as well as a target for cancer chemotherapy of the literature could be attributable to the assay conditions used human solid tumors. to determine enzyme activity. Higley and Buttery (26) reported that none of the standard assays developed by Grisolla and INTRODUCTION Cardoso (5), Smith and Yamada (10), or Fritzson (6) proved satisfactory. In mammalian systems the pathway for the catabolism of In the present study while determining dihydrouracil dehydro uracil, thymine, and their analogues (Chart 1) is via degradative genase activity in normal and neoplastic tissues from different reduction by which the pyrimidine ring is first reduced at positions human organs, we have initially experienced some difficulties in 5 and 6 with hydrogen from NADPH, then opened between obtaining optimal conditions for the measurements of this en positions 3 and 4, and finally split between position 1 and 2 to zyme activity. We found that substrate inhibition by uracil, en yield the corresponding <•>'aminoacid, carbon dioxide, and am zyme hysteresis, and allosterism were the main factors behind monia. this difficulty. This prompted us to study the kinetic parameters Dihydrouracil dehydrogenase (5,6-dihydrouracil: NADP+ oxi- of this enzyme in the cytosol of various tissues and organisms. doreductase, EC 1.3.1.2) is the first and purportedly rate limiting We herein demonstrate that the enzyme from the various enzyme of this chain of three reactions. It is responsible for the sources studied displayed substrate inhibition by uracil, and that reversible reduction of both uracil and thymine to dihydrouracil under appropriate assay conditions, the activity of dihydrouracil and dihydrothymine, respectively (1-4). This enzyme is also dehydrogenase can be detected in various normal and neoplastic responsible for the breakdown of the widely used antineoplastic human tissues. However, no definitive pattern in the relationship agent 5-fluorouracil, and the radiosensitizing agents 5-bromo- between enzyme activity in the normal and in corresponding and 5-iodouracil, thereby limiting their therapeutic effectiveness. neoplastic tissues could be established. Dihydropyrimidinase, on Cytosine and its analogues are not substrates for this enzyme the other hand, was absent from or showed little activity in and have to be converted to uracil before entering the reductive normal extrahepatic tissues as well as all neoplastic lymphoid degradation pathway. Most reports locate dihydrouracil dehydro tissues tested. In contrast all solid tumours tested had apprecia genase activity in liver cytosol (2, 5-9). However, an additional ble dihydropyrimidinase activity. A preliminary report has been dehydrogenase activity in the paniculate fraction has also been presented (27). reported (10,11 ). Dihydrouracil dehydrogenase has been purified 'Supported by Grants CA-31706 and CA-13943 awarded by the National MATERIALS AND METHODS Cancer Institute, Department of Health and Human Services, and Grant CH-136 from the American Cancer Society. Chemicals. [6-"C]Uracil (56 mCi/mmol) was purchased from Moravek 2To whom requests for reprints should be addressed. Biochemicals, Brea, CA; [6-14C]5-fluorouracil (55 mCi/mmol) was from Received 3/18/85; revised 6/9/85; accepted 7/22/85. CANCER RESEARCH VOL. 45 NOVEMBER 1985 5405 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1985 American Association for Cancer Research. ENZYMES OF URACIL CATABOLISM IN HUMAN TISSUES + NH, -. CO, K = H UKACIl OIHYDROURACIt «-tWEIOOntOPIOIUTE .-•AlANI« R=CH, THVMIHE DIHYDItOTHVMINE 0- UMEIDOIKMUTVKATf «-AMINOIKWUTYRATE R= F flUOROURACIL DIHYMOFLUOROUKACIL «-FLUORO-«-UREIOOFItOPIONATE .. HUORO s ALAMINÕ Chart 1. Pathway of pyrimidine base catabolism in mammalian systems. Amersham Corp., Arlington Heights, IL; uracil, dihydrouracil, carbamyl- blood of a patient with immunoglobulin plasma cell leukemia (34); K-562. 0-alanine, /3-alanine, NADPH, and ninhydrin, were from the Sigma Chem an undifferentiated blast cell line established from the pleural fluid of a ical Co., St. Louis, MO; Polygram CEL 300 UN/UMand silica gel G/UVuM patient with chronic myelocytic leukemia (35); KG-1, a mixture of pre TLC3 plates were from Brinkmann Instrument Co., Westbury, NJ; Om- dominantly myeloblasts and promyelocytes derived from the bone mar nifluor was from New England Nuclear, Boston, MA; dimethylamino- row of a patient with erythroleukemia (36); and HL-60, a promyelocytic benzaldehyde was from Aldhch Chemical Co., Milwaukee, Wl, and all cell line established from the peripheral blood of a patient with acute other chemicals were from Fisher Scientific Co., Boston, MA. promyelocytic leukemia (37). Normal Tissues. Normal human organs were obtained from autop RWLy-1, is a lymphoma line established and characterized by Wie- sies, peripheral blood lymphocytes were prepared from the blood of mann." It was isolated from the pleural effusion of a patient with mixed histiocytic-lymphocyticnon-Hodgkin's lymphoma. In tissue culture, about volunteers by the method of Boyum (28), and normal murine organs were obtained from Swiss albino (CD-1) mice or Lewis rats (Charles 50% of RWLy-1 cells have the morphological appearance of small River Breeding Laboratories, Wilmington, MA). Mice were killed by malignant lymphocytes and the other 50% have the appearance of large cervical dislocation and rats by decapitation. The organs were washed histiocytes. Cell surface IgM can be detected by immunofluorescence in with ice-cold normal saline (0.9% NaCI solution) before homogenization. greater than 70% of the cells. RWLy-1 is an Epstein-Barr virus-free cell Solid Tumors. Carcinomas of the colon, established from biopsies, line. were grown as xenografts in nude mice: DLD-1, a carcinoma of the Preparation of Extracts. Cells in suspension were collected by cen- sigmoid colon, morphologically heterogeneous, varying from moderately trifugation. The cells were washed by resuspending in the homogeniza to poorly differentiated (29); clone A, a subclone of DLD-1, producing tion buffer (20 mw potassium phosphate (pH 8) containing 1 rriM EDTA poorly differentiated adenocarcinomas (29); clone D, another subclone and 1 mw mercaptoethanol). After washing twice the pellet was homog of DLD-1, producing moderately differentiated adenocarcinomas (29); enized in 2 volumes of buffer, using a polytron homogenizer (Brinkmann). DLD-2, a well differentiated adenocarcinoma of the sigmoid colon; HCT- The homogenate was then centrifugea at 105,000 x g for 1 h at 4°C. 15, a moderately well differentiated adenocarcinoma of
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