Biological activity of 24,24-difluoro-1α,25-dihydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3-26,23-lactone in inducing Differentiation of human myeloid leukemia cells

Shiina, Yoshiko; Abe, Etsuko; Miyaura, Chisato; Tanaka, Hirofumi; Yamada, Sachiko; Ohmori, Masayuki; Nakayama, Keiko; Takayama, Hiroaki; Matsunaga, Isao; Nishii, Yasuho; DeLuca, Hector F.; Suda, Toshio

doi:10.1016/0003-9861(83)90390-9

Cited by 45 publications

(12 citation statements)

References 17 publications

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“…4 and 5). The order of the potency was very similar to the affinity of vitamin D3 derivatives in binding to the specific cytosol receptors found in intestines (16) and human myeloid leukemia cells (HL-60) (17,18). This suggests that la,25(OH)2D3 induces the production of a MFF by spleen cells and promotes fusion of mouse alveolar macrophages by a receptor-mediated mechanism.…”

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confidence: 55%

1 alpha,25-dihydroxyvitamin D3 promotes fusion of mouse alveolar macrophages both by a direct mechanism and by a spleen cell-mediated indirect mechanism.

Abe¹,

Miyaura²,

Tanaka³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

147

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Extensive fusion was induced in mouse alveolar macrophages by treatment with conditioned media obtained from spleen cell cultures treated with 15 ,ug of phytohemagglutinin or concanavalin A per ml or with 12 nM la,25-dihydroxyvitamin D3 [la,25(OH)2D31. The fusion rate was 80-90% on day 3. In addition, 1a,25(OH)2D3 added directly to alveolar macrophages induced fusion of about 35% of the cells on day 3, whereas direct addition of phytohemagglutinin and concanavalin A did not enhance fusion at all. When conditioned media from spleen cell or T cell cultures treated with 12 nM Ia,25(OH)2D3 were applied to a Sephadex G-100 column, a fusion factor (Mr 37,000-70,000) could be separated from Ia,25(OH)2D3. la,25(OH)2D3 induced fusion at 0.012-120 nM in a dose-dependent manner both by direct action and by spleen cell-mediated indirect action, but the fusion rate was always much greater in the latter than in the former at each concentration of the vitamin. Of the vitamin D3 derivatives tested, Ia,25(OH)2D3 was the most potent, followed successively by la,24R,25-trihydroxyvitamin D3, la-hydroxyvitamin D3, 25-hydroxyvitamin D3, and 24R,25-dihydroxyvitamin D3. These results clearly indicate that 1a,25(OH)2D3 induces fusion of mouse alveolar macrophages by both a direct and an indirect mechanism, the latter mediated by spleen cells, probably by T cells.Vitamin D3 is well known as an antirachitic agent that stimulates bone mineralization. In 1952, Carlsson demonstrated for the first time that vitamin D stimulates not only bone mineralization but also bone mineral mobilization (1). Vitamin D3 is metabolized first in the liver to 25-hydroxyvitamin D3 [25-(OH)D3] and then in the kidney mainly to 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] and la,25-dihydroxyvitamin D3

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confidence: 55%

1 alpha,25-dihydroxyvitamin D3 promotes fusion of mouse alveolar macrophages both by a direct mechanism and by a spleen cell-mediated indirect mechanism.

Abe¹,

Miyaura²,

Tanaka³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

147

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“…Although the biological activity of F 2 -1␣,25(OH) 2 D 3 was higher, the binding affinity of this analog to VDR was almost identical to that of 1␣,25(OH) 2 D 3 (16,17). It is accepted that the resistance of the C-F bond at C-24 of this analog to metabolic inactivation contributes to its higher biological activity.…”

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confidence: 93%

“…Of numerous synthetic analogs of 1␣,25(OH) 2 D 3 , 24,24-difluoro-1␣,25-dihydroxyvitamin D 3 (F 2 -1␣,25(OH) 2 D 3 ) (14) was the first that had a higher biological activity than the parental 1␣,25(OH) 2 D 3 (15)(16)(17). Although the biological activity of F 2 -1␣,25(OH) 2 D 3 was higher, the binding affinity of this analog to VDR was almost identical to that of 1␣,25(OH) 2 D 3 (16,17).…”

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confidence: 99%

1α,25-Dihydroxyvitamin D3-24-Hydroxylase (CYP24) Hydroxylates the Carbon at the End of the Side Chain (C-26) of the C-24-fluorinated Analog of 1α,25-Dihydroxyvitamin D3

Miyamoto¹,

Shinki²,

Yamamoto³

et al. 1997

Journal of Biological Chemistry

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. Recently, a model for the mechanism of the hydroxylation site selection by CYP24 and CYP27 was proposed. This model postulates that CYP24 directs its hydroxylation site(s) by the distance of C-24 and C-23 from the vitamin D ring structure and that CYP27 does so by the distance between the hydroxylation sites and the end of the side chain (13).Of numerous synthetic analogs of 1␣,25(OH) 2 D 3 , 24,24-difluoro-1␣,25-dihydroxyvitamin D 3 (F 2 -1␣,25(OH) 2 D 3 ) (14) was the first that had a higher biological activity than the parental 1␣,25(OH) 2 D 3 (15-17). Although the biological activity of F 2 -1␣,25(OH) 2 D 3 was higher, the binding affinity of this analog to VDR was almost identical to that of 1␣,25(OH) 2 D 3 (16, 17). It is accepted that the resistance of the C-F bond at C-24 of this analog to metabolic inactivation contributes to its higher biological activity. The metabolic fate of F 2 -1␣,25(OH) 2 D 3 , however, has not yet been clarified. We recently reported that F 2 -1␣,25(OH) 2 D 3 is metabolized into a more polar compound(s) * This work was supported in part by Grants-in-Aid 08457494 and 06454527 from the Ministry of Science, Education and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.‡ ‡ To whom correspondence should be addressed:

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“…In human myeloid leukemia cells it was 4-7 times more potent than the active metabolite in inducing cell differentiation to granulocytes [9]. 24R-F-l,25(OH)2D3 represents another analog which also cannot undergo the natu rally occurring C-24R hydroxylation.…”

Section: Introductionmentioning

confidence: 99%

Biological Activity of Fluorine-Substituted 1,25-Dihydroxyvitamin D<sub>3</sub> in Rats, in Chicken and in Japanese Quails

Rambeck¹,

Weiser²,

Zücker³

1986

Ann Nutr Metab

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The biological activity of two fluorinated analogs of 1,25(OH)₂D₃ was compared with 1,25(OH)₂D₃ in various vitamin D assays. The effect of 24,24-F₂-1,25(OH)₂D₃ on plasma calcium, bone weight and duodenal calcium binding protein in chicken, on calcium excretion via egg shell in Japanese quails and on mobilization of calcium from the bone in rats was twice as high as the effect of the most potent naturally occurring vitamin D₃ metabolite 1,25(OH)₂D₃. In contrast, 24R-F-1,25(OH)₂D₃ has less than 50% of the potency of 1,25(OH)₂D₃. Due to the wider therapeutic dosage range, this compound might be of clinical value.

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Biological activity of 24,24-difluoro-1α,25-dihydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3-26,23-lactone in inducing Differentiation of human myeloid leukemia cells

Cited by 45 publications

References 17 publications

1 alpha,25-dihydroxyvitamin D3 promotes fusion of mouse alveolar macrophages both by a direct mechanism and by a spleen cell-mediated indirect mechanism.

1 alpha,25-dihydroxyvitamin D3 promotes fusion of mouse alveolar macrophages both by a direct mechanism and by a spleen cell-mediated indirect mechanism.

1α,25-Dihydroxyvitamin D3-24-Hydroxylase (CYP24) Hydroxylates the Carbon at the End of the Side Chain (C-26) of the C-24-fluorinated Analog of 1α,25-Dihydroxyvitamin D3

Biological Activity of Fluorine-Substituted 1,25-Dihydroxyvitamin D<sub>3</sub> in Rats, in Chicken and in Japanese Quails

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