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Titolo:
Metabolism of 1 alpha,25-dihydroxyvitamin D-3 in human promyelocytic leukemia (HL-60) cells: In vitro biological activities of the natural metabolites of 1 alpha,25-dihydroxyvitamin D-3 produced in HL-60 cells
Autore:
Rao, DS; Campbell, MJ; Koeffler, HP; Ishizuka, S; Uskokovic, MR; Spagnuolo, P; Reddy, GS;
Indirizzi:
Brown Univ, Women & Infants Hosp, Sch Med, Dept Pediat, Providence, RI 02905 USA Brown Univ Providence RI USA 02905 Dept Pediat, Providence, RI 02905 USA Univ Birmingham, Queen Elizabeth Hosp, Dept Med, Birmingham B15 2TH, W Midlands, England Univ Birmingham Birmingham W Midlands England B15 2TH W Midlands, England Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Div Hematol Oncol, Los Angeles, CA 90048 USA Univ Calif Los Angeles Los Angeles CA USA 90048 Los Angeles, CA 90048 USA Teijin Inst Biomed Res, Hino, Tokyo 1918512, Japan Teijin Inst Biomed ResHino Tokyo Japan 1918512 ino, Tokyo 1918512, Japan Hoffmann La Roche Inc, Nutley, NJ 07110 USA Hoffmann La Roche Inc Nutley NJ USA 07110 Roche Inc, Nutley, NJ 07110 USA Metrohlth Med Ctr, Cleveland, OH 44109 USA Metrohlth Med Ctr Cleveland OHUSA 44109 Med Ctr, Cleveland, OH 44109 USA
Titolo Testata:
STEROIDS
fascicolo: 3-5, volume: 66, anno: 2001,
pagine: 423 - 431
SICI:
0039-128X(200103/05)66:3-5<423:MO1ADI>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
VITAMIN-D ANALOGS; INTESTINAL CALCIUM-ABSORPTION; C-24 OXIDATION PATHWAY; LINE HL-60; CALCITROIC ACID; HL60 CELLS; DIFFERENTIATION; 1,25-DIHYDROXYVITAMIN-D3; PROLIFERATION; INDUCTION;
Keywords:
1 alpha,25(OH)(2)D-3; 1 alpha,23(S),25(OH)(3)-24-oxo-D-3; natural metabolites; metabolism; HL-60 cells;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Reddy, GS Brown Univ, Women & Infants Hosp, Sch Med, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA Brown Univ 101 Dudley St Providence RI USA 02905 e, RI 02905 USA
Citazione:
D.S. Rao et al., "Metabolism of 1 alpha,25-dihydroxyvitamin D-3 in human promyelocytic leukemia (HL-60) cells: In vitro biological activities of the natural metabolites of 1 alpha,25-dihydroxyvitamin D-3 produced in HL-60 cells", STEROIDS, 66(3-5), 2001, pp. 423-431

Abstract

The secosteroid hormone, 1 alpha ,25-dihydroxyvitamin D-3 [1 alpha ,25(OH)(2)D-3], induces differentiation of the human promyelocytic leukemia (HL-60) cells into monocytes/macrophages. At present, the metabolic pathways of 1alpha ,25(OH)(2)D-3 and the biologic activity of its various natural intermediary metabolites in HL-60 cells are not fully understood. 1 alpha ,25(OH)(2)D-3 is metabolized in its target tissues via modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the main side chain modification pathway initiated by hydroxylation at C-24 leads to the formation of the end product, calcitroic acid. The C-23 and C-26 oxidation pathways, the minor side chain modification pathways initiated by hydroxylations at C-23 and C-26 respectively together lead to the formation of the end product, 1 alpha ,25(OH)(2)D-3-lactone. The C-3 epimerization pathway, the newly discovered A-ring modification pathway is initiated by epimerization of the hydroxyl group at C-3 to form 1 alpha ,25-dihydroxy-3-epi-vitamin-D-3. We performed the present study first to examine in detail the metabolism of1 alpha ,25(OH)(2)D-3 in HL-60 cells and then to assess the ability of thevarious natural intermediary metabolites of 1 alpha ,25(OH)(2)D-3 in inducing differentiation and in inhibiting clonal growth of HL-60 cells. We incubated HL-60 cells with [1 beta-H-3] 1 alpha ,25(OH)(2)D-3 and demonstrated that these cells metabolize 1 alpha ,25(OH)(2)D-3 mainly via the C-24 oxidation pathway and to a lesser extent via the C-23 oxidation pathway, but notvia the C-3-epimerization pathway. Three of the natural intermediary metabolites of 1 alpha ,25(OH)(2)D-3 derived via the C-24 oxidation pathway namely, 1 alpha ,24(R),25-trihydroxyvitamin D-3, 1 alpha ,25-dihydroxy-24-oxovitamin D-3 and 1 alpha ,23(S),25-trihydroxy-24-oxovitamin D-3 [1 alpha ,23(S),25(OH)(3)-24-oxo-D-3] were almost as potent as 1 alpha ,25(OH)(2)D-3 in terms of their ability to differentiate HL-60 cells into monocytes/macrophages. We then selected 1 alpha ,23(S),25(OH)(3)-24-oxo-D-3 which has the least calcemic activity among all the three aforementioned natural intermediarymetabolites of 1 alpha ,25(OH)(2)D-3 to examine further its effects on these cells. Our results indicated that 1 alpha ,23(S),25(OH)(3)-24-oxo-D-3 was also equipotent to it!; parent in inhibiting clonal growth of HL-60 cellsand in inducing expression of CD11b protein. In summary, we report that 1 alpha ,25(OH)(2)D-3 is metabolized in HL-60 cells into several intermediarymetabolites derived via both the C-24 and C-23 oxidation pathways but not via the C-3 epimerization pathway. Some of the intermediary metabolites derived via the C-24 oxidation pathway are found to be almost equipotent to 1 alpha ,25(OH)(2)D-3 in modulating growth and differentiation of HL-60 cells. In a previous study, the same metabolites when compared to 1 alpha ,25(OH)(2)D-3 were found to be less calcemic. Thus, the findings of our study suggest that some of the natural metabolites of 1 alpha ,25(OH)(2)D-3 may be responsible for the final expression of the noncalcemic actions that are presently being attributed to their parent, 1 alpha ,25(OH)(2)D-3. (C) 2001 Elsevier Science Inc. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/09/20 alle ore 20:11:53