INSULIN-DEPENDENT SUPPRESSION IN GLUTAMYL HYDROLASE ACTIVITY AND ELEVATED CELLULAR METHOTREXATE POLYGLUTAMATES

被引:7
作者
GALIVAN, J [1 ]
RHEE, MS [1 ]
机构
[1] NEW YORK STATE DEPT HLTH, WADSWORTH CTR, DIV MOLEC MED, ALBANY, NY 12201 USA
关键词
GLUTAMYL HYDROLASE; FOLYLPOLYGLUTAMATES; METHOTREXATE POLYGLUTAMATE; INSULIN; HEPATIC; POLYGLUTAMYLATION;
D O I
10.1016/0006-2952(95)02064-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Folates and antifolates are converted to polyglutamates, which are better retained in cells and may also bind more tightly to cellular proteins than the parent compounds. The regulation of the process of polyglutamate formation and breakdown is not fully clarified yet and is being studied by a number of approaches. An early observation concerning the potential regulation of polyglutamate formation was that insulin caused a marked increase in the rate and accumulation of polyglutamates of methotrexate (MTX) in rat hepatoma cells. The present study demonstrated that insulin caused a decrease in the activity of gamma-glutamyl hydrolase (GH), the enzyme that degrades polyglutamates, that was inversely commensurate with the increase in the synthesis of MTX polyglutamates. The effects of insulin on GH activity with regard to concentration, time of onset, and the effect of N-6, O-2' dibutyryl CAMP and theophylline were consistent with the reduction in GH being responsible for the increase in cellular MTX polyglutamate accumulation. Insulin addition also led to an increase in folate polyglutamates. The insulin effects were also seen with H35D cells, a subline with enhanced glutamyl hydrolase activity as a result of having been made resistant to 5, 10-dideazatetrahydrofolic acid. When H35 cells with insulin were compared with H35D cells lacking insulin, there was an 8-fold increase in GH and a 44-fold decrease in the number of gamma-glutamate residues added to MTX.
引用
收藏
页码:1659 / 1663
页数:5
相关论文
共 23 条
  • [1] METABOLIC MODIFICATION BY INSULIN ENHANCES METHOTREXATE CYTO-TOXICITY IN MCF-7 HUMAN-BREAST CANCER-CELLS
    ALABASTER, O
    VONDERHAAR, BK
    SHAFIE, SM
    [J]. EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY, 1981, 17 (11): : 1223 - 1228
  • [2] STRUCTURAL FEATURES OF 5,10-DIDEAZA-5,6,7,8-TETRAHYDROFOLATE THAT DETERMINE INHIBITION OF MAMMALIAN GLYCINAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE
    BALDWIN, SW
    TSE, A
    GOSSETT, LS
    TAYLOR, EC
    ROSOWSKY, A
    SHIH, C
    MORAN, RG
    [J]. BIOCHEMISTRY, 1991, 30 (07) : 1997 - 2006
  • [3] BARRUECO JR, 1992, J BIOL CHEM, V267, P19986
  • [4] BARRUECO JR, 1992, J BIOL CHEM, V267, P15356
  • [6] GALIVAN J, 1984, ADV ENZYME REGUL, V23, P13
  • [7] GALIVAN J, 1980, MOL PHARMACOL, V17, P105
  • [8] JACKMAN AL, 1991, CANCER RES, V51, P5579
  • [9] JOHNSON TB, 1988, CANCER RES, V48, P2426
  • [10] PURIFICATION AND PROCESSING OF RAT-LIVER PROCATHEPSIN-B
    KAWABATA, T
    NISHIMURA, Y
    HIGAKI, M
    KATO, K
    [J]. JOURNAL OF BIOCHEMISTRY, 1993, 113 (03) : 389 - 394