Regulatory activities of 2β-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3, a novel synthetic vitamin D3 derivative, on calcium metabolism

Okano, Toshio; Tsugawa, Naoko; Masuda, Sonoko; Takeuchi, Atsuko; Kobayashi, Tadashi; Takita, Yumiko; Nishii, Yasuho

doi:10.1016/0006-291x(89)91140-6

Cited by 108 publications

(49 citation statements)

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“…These findings suggest that this agent inhibits the loss of cortical bone. It has been reported that feeding a calcium-deficient diet to ovariectomized rats accelerates bone loss (14,15). Accordingly, a calcium-deficient diet (0.01% calcium) was fed to ovariectomized rats for 3 months, in experi ment 3.…”

Section: Discussionmentioning

confidence: 99%

L-Dopa Potentiates Presynaptic Inhibitory α2-Adrenoceptor- but Not Facilitatory Angiotensin II Receptor-Mediated Modulation of Noradrenaline Release from Rat Hypothalamic Slices

Akiyama

Hara

Ohkawa

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-The effects of menatetrenone, a vitamin K2 homologue, on bone loss induced by ovariectomy in rats were studied in 3 experiments. Menatetrenone was given as a dietary supplement. In experiment 1, at 2 weeks postovariectomy, menatetrenone (10 mg/kg/day given for 2 weeks) inhibited the decrease in bone density of the femoral metaphysis induced by the ovariectomy. In experiment 2, menatetrenone (3 or 30 mg/kg/day given for 6 months) inhibited the decrease in bone strength of the femur and the decrease in calcium and hydroxyproline content of the femoral diaphysis at 6 months postovariectomy. In experiment 3, menatetrenone treatment, at 30 or 100 mg/kg/day for 6 months, protected against the decrease in bone strength and calcium and hydroxyproline content in the bone loss model induced by ovariectomy and calcium-deficient diet. These findings suggest that menatetrenone protects against the bone loss induced by ovariectomy. Keywords:Menatetrenone, Ovariectomy, Bone lossSince Bouckaert and Said first reported the effect of vitamin K on fracture healing in 1960 (1), several studies have suggested that this vitamin affects bone metabolism. Hall et al. reported that some infants whose mothers had received oral anticoagulant therapy during pregnancy had hypoplasia of the nasal bone (2). Hart et al. demonstrated that circulating levels of vitamin K, in osteoporotic patients with fractures were significantly lower than those in age-matched control subjects (3). It is well-known that vitamin K is essential for the r-carboxylation of osteocal cin (4), a non-collagenous protein present in bone (5, 6). Although the role of osteocalcin in bone metabolism remains obscure, it is possible that vitamin K may play a role in bone metabolism via this substance.Two types of vitamin K occur in nature: vitamin K, (phylloquinone, 2-methyl-3-phytyl-1,4-naphthoquinone), which is derived from plants, and vitamin K2 (menaqui nones), a series of vitamers with multi-isoprene units at the 3-position. In the present studies, we assessed the effects of menatetrenone (2-methyl-3 -all-trans-tetra prenyl-1,4-naphthoquinone), a vitamin K2 with four isoprene units, on bone loss induced by ovariectomy in rats in three different experiments: In experiment 1, we examined its effects on early metaphysial bone loss in the femur; in experiment 2, we studied its effects on the de velopment of bone loss induced by ovariectomy over a 6-month period; and in experiment 3, we studied its cura tive effects over 6 months on bone loss induced by ovariec tomy and a calcium-deficient diet. MATERIALS AND METHODS AnimalsFor experiment 1, we used 20-week-old female Fischer rats (Clea Japan, Inc., Tokyo); and for experiments 2 and 3, we used 40-week-old female Sprague-Dawley rats (Charles River Japan, Inc., Tokyo). The animals were housed in a room maintained at 261C with a 12-hr light dark cycle and were given free access to food and distilled water. All operations were performed under pentobar bital anesthesia. Experiment 1Twenty rats underwent bilateral ovariecto...

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Section: Discussionmentioning

confidence: 99%

L-Dopa Potentiates Presynaptic Inhibitory α2-Adrenoceptor- but Not Facilitatory Angiotensin II Receptor-Mediated Modulation of Noradrenaline Release from Rat Hypothalamic Slices

Akiyama

Hara

Ohkawa

et al. 1993

Japanese Journal of Pharmacology

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“…The half-life of eldecalcitol in serum is longer that than that of calcitriol. 60 Such differences may be related to the higher efficacy of eldecalcitol than alfacalcidol.…”

Section: Effects Of the In Vivo Administration Of Vitamin D Compoundsmentioning

confidence: 99%

Vitamin D endocrine system and osteoclasts

Takahashi¹,

Udagawa²,

Suda³

2014

BoneKEy Reports

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Vitamin D was discovered as an anti-rachitic agent preventing a failure in bone mineralization, but it is now established that the active form of vitamin D 3 (1a,25(OH) 2 D 3 ) induces bone resorption. Discovery of the receptor activator of nuclear factor -kB ligand (RANKL) uncovered the molecular mechanism by which 1a,25(OH) 2 D 3 stimulates bone resorption. Treating osteoblastic cells with 1a,25(OH) 2 D 3 stimulates RANKL expression, which in turn induces osteoclastogenesis. Nevertheless, active vitamin D compounds such as calcitriol (1a,25(OH) 2 D 3 ), alfacalcidol (1a(OH)D 3 ) and eldecalcitol (1a,25-dihydroxy-2b-(3-hydroxypropoxy) vitamin D 3 ) have been used as therapeutic drugs for osteoporosis, as they increase bone mineral density (BMD) in osteoporotic patients. Paradoxically, the increase in BMD is caused by the suppression of bone resorption. Several studies have been performed to elucidate the mechanism by which active vitamin D compounds suppress bone resorption in vivo. Our study showed that daily administration of eldecalcitol to mice suppressed neither the number of osteoclast precursors in the bone marrow nor the number of osteoclasts formed in ex vivo cultures. Eldecalcitol administration suppressed RANKL expression in osteoblasts. This review discusses how the difference between in vitro and in vivo effects of active vitamin D compounds on bone resorption is induced.

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“…Of these, A-ring analogs have great potential for clinical use. For example, ED-71, which bears a 3-hydroxypropoxy group at the 2␤-position of 1␣,25(OH) 2 D 3 , was developed by Chugai Pharmaceutical Co. (Tokyo, Japan) as a potential therapeutic agent for osteoporosis because ED-71 significantly increases plasma calcium level for a long time (Okano et al, 1989). In addition, it was also reported that diastereomers of 2-methyl-1␣,25(OH) 2 D 3 had unique activity profiles depending on their stereochemistry.…”

Section: Discussionmentioning

confidence: 99%

“…Note that O2C3 is the C 2 -epimer of ED-71 (Fig. 1), which is being developed by Chugai Pharmaceutical Co. (Tokyo, Japan) as a potential therapeutic agent for osteoporosis (Okano et al, 1989).Recently, we revealed the enzymatic properties of CYP27A1, CYP27B1, and CYP24A1 expressed in Escherichia coli cells (Sakaki et al, 1999a(Sakaki et al, ,b, 2000Sawada et al, 1999Sawada et al, , 2000Uchida et al, 2004 …”

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METABOLISM OF 2α-PROPOXY-1α,25-DIHYDROXYVITAMIN D₃AND 2α-(3-HYDROXYPROPOXY)-1α,25-DIHYDROXYVITAMIN D₃BY HUMAN CYP27A1 AND CYP24A1

Abe¹,

Sakaki²,

Kusudo³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Recently, we demonstrated that some A-ring-modified vitamin D 3 analogs had unique biological activity. Of these analogs, 2␣-propoxy-1␣,25(OH) 2 D 3 (C3O1) and 2␣-(3-hydroxypropoxy)-1␣,25(OH) 2 D 3 (O2C3) were examined for metabolism by CYP27A1 and CYP24A1. Surprisingly, CYP27A1 catalyzed the conversion from C3O1 to O2C3, which has 3 times more affinity for vitamin D receptor than C3O1. Thus, the conversion from C3O1 to O2C3 by CYP27A1 is considered to be a metabolic activation process. Five metabolites were detected in the metabolism of C3O1 and O2C3 by human CYP24A1 including both C-23 and C-24 oxidation pathways. On the other hand, three metabolites of the C-24 oxidation pathway were detected in their metabolism by rat CYP24A1, indicating a species-based difference in the CYP24A1-dependent metabolism of C3O1 and O2C3 between humans and rats. Kinetic analysis revealed that the K m and k cat values of human CYP24A1 for O2C3 are, respectively, approximately 16 times more and 3 times less than those for 1␣,25(OH) 2 D 3 . Thus, the catalytic efficiency, k cat /K m , of human CYP24A1 for O2C3 is only 2% of 1␣,25(OH) 2 D 3 . These results and a high calcium effect of C3O1 and O2C3 in animal experiments using rats suggest that C3O1 and O2C3 are promising for clinical treatment of osteoporosis.Vitamin D 3 is initially converted to 25(OH)D 3 by CYP27A1 in the liver, and then 25(OH)D 3 is converted to 1␣,25(OH) 2 D 3 by CYP27B1 in the kidneys. On the other hand, CYP24A1 is recognized as the key enzyme in the biological inactivation of 1␣,25(OH) 2 D 3 . The 1␣,25(OH) 2 D 3 level is precisely regulated via gene regulation of CYP27B1 and CYP24A1.Analogs of 1␣,25(OH) 2 D 3 are potentially useful for clinical treatment of type I rickets, osteoporosis, leukemia, psoriasis, renal osteodystrophy, and breast cancer (Binderup et al., 1991;Bishop et al., 1994;Bouillon et al., 1995;Yamada et al., 2003). For vitamin D analogs, the metabolism in such target tissues as kidneys, small intestine, and bones is pharmacologically essential, as reported by Komuro et al. (1998). Recently, we revealed that some A-ring-modified vitamin D 3 analogs had unique biological activity (Konno et al., 2000;Suhara et al., 2001;Takayama et al., 2001), and that ligands with a modification in the A-ring can alter the VDR-coactivator interaction, resulting in selective potentiation of the transcription function (Kittaka et al., 2000;Konno et al., 2000;Suhara et al., 2001;Takayama et al., 2001;Fujishima et al., 2003;Saito et al., 2004). This study examined two promising analogs for clinical use, 2␣-propoxy-1␣,25(OH) 2 D 3 (C3O1) and 2␣-(3-hydroxypropoxy)-1␣,25(OH) 2 D 3 (O2C3). O2C3 binds better than natural hormone to the mutant vitamin D receptor (R274A), which lost the hydrogen bond to the 1␣-hydroxyl group of 1␣,25(OH) 2 D 3 . In addition, in our recent study, the high calcium effects of C3O1 and O2C3 were observed in animal experiments using rats. Note that O2C3 is the C 2 -epimer of ED-71 (Fig. 1), which is being developed by Chugai Pharmaceut...

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Regulatory activities of 2β-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3, a novel synthetic vitamin D3 derivative, on calcium metabolism

Cited by 108 publications

References 10 publications

L-Dopa Potentiates Presynaptic Inhibitory α2-Adrenoceptor- but Not Facilitatory Angiotensin II Receptor-Mediated Modulation of Noradrenaline Release from Rat Hypothalamic Slices

L-Dopa Potentiates Presynaptic Inhibitory α2-Adrenoceptor- but Not Facilitatory Angiotensin II Receptor-Mediated Modulation of Noradrenaline Release from Rat Hypothalamic Slices

Vitamin D endocrine system and osteoclasts

METABOLISM OF 2α-PROPOXY-1α,25-DIHYDROXYVITAMIN D₃AND 2α-(3-HYDROXYPROPOXY)-1α,25-DIHYDROXYVITAMIN D₃BY HUMAN CYP27A1 AND CYP24A1

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Regulatory activities of 2β-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3, a novel synthetic vitamin D3 derivative, on calcium metabolism

Cited by 108 publications

References 10 publications

L-Dopa Potentiates Presynaptic Inhibitory α2-Adrenoceptor- but Not Facilitatory Angiotensin II Receptor-Mediated Modulation of Noradrenaline Release from Rat Hypothalamic Slices

L-Dopa Potentiates Presynaptic Inhibitory α2-Adrenoceptor- but Not Facilitatory Angiotensin II Receptor-Mediated Modulation of Noradrenaline Release from Rat Hypothalamic Slices

Vitamin D endocrine system and osteoclasts

METABOLISM OF 2α-PROPOXY-1α,25-DIHYDROXYVITAMIN D3AND 2α-(3-HYDROXYPROPOXY)-1α,25-DIHYDROXYVITAMIN D3BY HUMAN CYP27A1 AND CYP24A1

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METABOLISM OF 2α-PROPOXY-1α,25-DIHYDROXYVITAMIN D₃AND 2α-(3-HYDROXYPROPOXY)-1α,25-DIHYDROXYVITAMIN D₃BY HUMAN CYP27A1 AND CYP24A1