Biological Activity of 1α-Hydroxycholecalciferol, A Synthetic Analog of the Hormonal Form of Vitamin D
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Haussler, Mark R.; Zerwekh, Joseph E.; Hesse, Robert H.; Rizzardo, Ezio; Pechet, Maurice M.

doi:10.1073/pnas.70.8.2248

Cited by 94 publications

(27 citation statements)

References 29 publications

(25 reference statements)

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“…Treatment of ARVDD with a "surrogate" vitamin D hormone, such as la-hydroxycholecalciferol (la-OH-D,) (22,24), would be advantageous. Crystalline la-OH-D, is more easily synthesized than la,25-(OH),-D,, and the former can be effectively administered by mouth.…”

Section: Speculationmentioning

confidence: 99%

Response to Crystalline 1α-Hydroxyvitamin D3 in Vitamin D Dependency

Glorieux

et al. 1975

Pediatr Res

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ExtractThe therapeutic response to chemically_synthesized la-hydroxycholecalciferol (la-OH-D,) was studied in three patients with autosomal recessive vitamin D dependency (ARVDD). The daily maintenance dose for vitamin D,, to prevent signs of vitamin D deficiency in these patients, was 40-54.5 fig/kg, or about 100 times normal (Table 1). Withdrawal of maintenance therapy with vitamin D, resulted in the ultimate reappearance of the vitamin D depletion syndrome in patients I and 2 ( Figs. 1 and 2). The third patient presented with the deficiency syndrome despite adequate vitamin D nutrition and was recognized to have ARVDD.Treatment with la-OH-D, by mouth in all three patients at dose levels of 1-3 pg/24 hr (8@100 ng/kg) corrected hypocalcemia and suppressed parathyroid hormone-dependent renal loss of amino acids (Figs. 1,2, and 4). Rickets healed in 7-9 weeks on la-OH-D, alone (Fig. 3 ) The therapeutic response was rapid. It was usually seen first in the rise of serum calcium (Figs. 5 and 6). Withdrawal of la-OH-D, was followed first by a fall of serum phosphorus, then by a fall in serum calcium; the latter occurred within about 2 weeks of withdrawal.Because the synthesis of la-OH-D, is simpler than for la,25-dihydroxycholecalciferol and because the former is an effective therapeutic analog of vitamin D hormone, we believe these studies in ARVDD reveal la-OH-D, to be the agent of choice for treatment of this and analogous diseases. SpeculationVitamin D dependency or pseudodeficiency rickets is believed to be an inborn error of vitamin D hormone biosynthesis. The putative abnormal enzyme is 25-hydroxycholecalciferol 1-hydroxylase in the recessively inherited trait. Consequently, this experiment of nature offers a special opportunity to examine the requirement in human subjects, for la-hydroxyvitamin D, metabolites.Patients with ARVDD (14, 18, 36) develop signs of severe postnatal vitamin D deficiency, despite a nutritional intake of vitamin D, or vitamin D, (40) that would prevent rickets in normal subjects; hence the term pseudodeficiency preferred by some investigators (34). Persistent hypocalcemia appearing soon after birth is accompanied by an excess of circulating parathyroid hormone (I) which in turn is associated with hyperphosphaturia and hyperaminoaciduria (1, 37). Elevated serum alkaline phosphatase activity, severe rachitic bone lesions, and enamel hypoplasia affecting teeth that form postnatally complete the clinical syndrome ( I , l I, 14, 18, 34, 36). Maintenance treatment with vitamin D, only at levels about 100 times the normal requirement fully reverses the manifestations of deficiency hence the term vitamin D dependency (18,36).The origin of the disturbed physiology in ARVDD lies in a selective disturbance of calcium absorption by intestine (18). A defect either in the biosynthesis of the active hormone form of vitamin D or in the ability of target organ(s) to respond to vitamin D hormone has been proposed (36) to explain the dependency on vitamin D,, D,, or 25-OH-D, of patients with ARVDD. ARVDD...

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Section: Speculationmentioning

confidence: 99%

Response to Crystalline 1α-Hydroxyvitamin D3 in Vitamin D Dependency

Glorieux

et al. 1975

Pediatr Res

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“…Zerwekh et al (8) suggested from data in rachitic chicks that la(OH)D3 must undergo 25-hydroxylation before exerting its effects, while Toffolon et al (9) proposed that this compound may act directly without subsequent metabolic conversion. The potencies of 1,25-(OH) 2D3 and lca (OH) D3 were found to be equal in the vitamin D-deficient rat by Toffolon et al (9) and in the rachitic chick by Haussler et al (10), respectively. On the other hand, Holick et al (11) found la(OH)Ds to be about half as potent as 1,25 (OH'2D3 in vitamin 1Abbreviations used in this paper: 1,25(OH)2D3, 1,25-dihydroxycholecalciferol; la (OH) D3, la-hydroxy-vitamin D,.…”

Section: Introductionmentioning

confidence: 95%

Comparison of effects of 1 alpha-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 in man.

Brickman¹,

Coburn²,

Friedman³

et al. 1976

J. Clin. Invest.

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A B S T R A C T The effects of short-term treatment with 1,25-dihydroxy-vitamin D3 [1,25 (OH) 11 patients were studied a second time after treatment for 2-5 mo. Doses varied from 0.14 to 5.4 ug/day to establish dose-response relationships. Urinary calcium was monitored in normal subjects, nine of whom received a constant calcium intake on a metabolic unit. There was an increase in intestinal absorption of 'Ca and urinary calcium in normals receiving 1,25 (OH)2D3, 0.14 fg/day or greater, and 0.28 ig/day or greater augmented intestinal absorption of "Ca in chronic renal failure. In contrast, 2.6 Ag/day of la(OH)Ds was required to increase intestinal absorption of 'Ca in both groups. The increase in urinary calcium to maximal levels was delayed during treatment with la(OH)Ds, 5-10 days vs. 2-5 days with 1,25 (OH) 2Ds. Moreover, half times for urinary calcium to decrease to pretreatment levels after stopping treatment were greater after la-(OH)Da (1.5-2.7 days) than 1,25(OH)2D3 (1.1-2.0 days). With long-term administration there was a progressive increase in intestinal absorption of "Ca in the patients receiving la(OH)D3; this was not observed with 1,25 (OH)2D3.The pharmacologic differences between la (OH) D3 and 1,25 (OH)2D3 may be explained by the requirement for 25-hydroxylation of la(OH)D3 before biologic effects occur; at low doses (<1 ug/day), la(OH)Ds competes with vitamin D3 for 25-hydroxylation. With prolonged treatment or larger doses (>2 ig/day), la-(OH) D3 could accumulate and then be hydroxylated resulting in production of higher levels of 1,25 (OH)2Da.

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“…The importance of. the lai-hydroxyl to biological activity is further emphasized by the observed high biological activity of the chemically synthesized analogs, 3-deoxy-la-OH-vitamin D3 (3-d-la-OH-D3) (20) and la-hydroxyvitamin D3 (la-OHD3) (21)(22)(23)(24)(25), and the pseudo-la-hydroxyl § analogs, 5,6-trans-vitamin D3 (5,6-t-D3) (26), dihydrotachysterol3 (H2T3) (27)(28)(29), and isotachysterol3 (i-T3) (30). (See Fig.…”

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confidence: 99%

Vitamin D: Concerning the Relationship Between Molecular Topology and Biological Function

Okamura

Norman

Wing

1974

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

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Structure-function relationships for vitamin D1, its metabolites, and analogs are discussed with particular emphasis on the A-ring conformation. It is emphasized that the A-ring of these seco-steroids consists of a pair of rapidly equilibrating chair conformers. As a consequence, different chair conformations produce different orientations of substituent groups in the A-ring. It is propbsed that the la-hydroxyl of la,25-dihydroxyvitamin D3 or its geometric equivalent in analogs must occupy the equatorial, as opposed to the axial, orientation for optimization of biological activity. This proposal is discussed in relation to existing published data on struc- (0,10). The biochemical mode of action of la,25-(OH)2D3 (11) is believed to occur as a consequenee of association with cytoplasmic and nuclear receptors, as is the case for other classical steroid hormones (12, 13) such as estrogen (14), hydrocortisone (15), aldosterone (16), or Abbreviations: D3, vitamin D3; 25-OHD3, 25-hydroxyvitamin D3; 1a,25-(OH)2D3, la,25-dihydroxyvitamin D3; la-OHD3, lahydroxyvitamin D3; 5,6-t-D3, 5,6-trans-vitamin D3; H2T, dihydrotachysterol; i-T, isotachysterol; H2V-IV, dihydrovitamin D-IV; 3-d-la-OHD3, 3-deoxy-lc-hydroxyvitamin D3; 3-d-la,25-(OH)2D3, 3-deoxy-la,25-dihydroxyvitamin D3; 3a!-or 3,8-Me-3-d-la-OHD3, 3a-or 3,3-methyl-3-deoxy-1a-hydroxyvitamln D3; the subscript 3 or 2 after the letters D, T, and V refer to vitamin D-like molecules containing the cholesterol side-chain carbon skeleton as in vitamin D3 or the ergosterol side-chain carbon skeleton as in vitamin D2, respectively. The abbreviation H2T instead of DHT for dihydrotachysterol is used since the former is more in keeping with the rules of IUB and IUPAC.* Send all correspondence to the first author. A preliminary account of this work was presented at the 1974 meetings of the American Society of Biological Chemists in Minneapolis, Minn. (see ref. 20). This is paper V in the series, "Studies on Vitamin D and Its Analogs." Paper IV is Norman, A. W., Mitra, M. N., Okamura, W. H. & Wing, R. M., "Vitamin D: 3-Deoxy-lahydroxyvitamin D3, a biologically active analog of la,25-dihydroxyvitamin D3," Science, in press. testosterone (17). In fact, the fat-soluble vitamin D3 should be considered a steroid hormone both from a structural and a functional point of view (18).The unusual importance of the 1a-hydroxyl to the active metabolite was emphasized by the observation that neither the parent vitamin D3 nor the intermediate 25-hydroxyvitamin D3 (25-OHD3) weie able to produce any stimulation of intestinal calcium transport in nephrectomized rats, while 1a,25-(OH)2D3 was fully active (19). The importance of. the lai-hydroxyl to biological activity is further emphasized by the observed high biological activity of the chemically synthesized analogs, 3-deoxy-la-OH-vitamin D3 (3-d-la-OH-D3) (20) and la-hydroxyvitamin D3 (la-OHD3) (21-25), and the pseudo-la-hydroxyl § analogs, 5,6-trans-vitamin D3 (5,6-t-D3) (26), dihydrotachysterol3 (H2T3) (27-29), and isotachysterol3 (i-T3) (30)...

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Biological Activity of 1α-Hydroxycholecalciferol, A Synthetic Analog of the Hormonal Form of Vitamin D ₃

Cited by 94 publications

References 29 publications

Response to Crystalline 1α-Hydroxyvitamin D3 in Vitamin D Dependency

Response to Crystalline 1α-Hydroxyvitamin D3 in Vitamin D Dependency

Comparison of effects of 1 alpha-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 in man.

Vitamin D: Concerning the Relationship Between Molecular Topology and Biological Function

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Biological Activity of 1α-Hydroxycholecalciferol, A Synthetic Analog of the Hormonal Form of Vitamin D 3

Cited by 94 publications

References 29 publications

Response to Crystalline 1α-Hydroxyvitamin D3 in Vitamin D Dependency

Response to Crystalline 1α-Hydroxyvitamin D3 in Vitamin D Dependency

Comparison of effects of 1 alpha-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 in man.

Vitamin D: Concerning the Relationship Between Molecular Topology and Biological Function

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Biological Activity of 1α-Hydroxycholecalciferol, A Synthetic Analog of the Hormonal Form of Vitamin D ₃