Isolation and identification of 24,25-dihydroxy vitamin D2 by use of the perfused rat kidney

Jones, Glenville; Rosenthal, A.; Segev, Danny; Mazur, Yehuda; Frolow, Felix; Halfon, Yaacov; Rabinovich, D.; Shakked, Zippora

doi:10.1021/bi00573a025

Cited by 25 publications

(13 citation statements)

References 16 publications

(24 reference statements)

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“…has been reported to be metabolized to 24,25(OH) 2 D2 and 24,25,26(OH) 3 D2 by perfused rat kidneys [212,213]. It has also been shown to be metabolized to 24R, 25,28(OH) 3 D2 and 24S,25,28(OH) 3 D2 by perfused rat kidneys and rat kidney homogenates with evidence for further metabolism to water-soluble products [214], presumably by CYP24A1.…”

Section: (Oh)d2mentioning

confidence: 98%

The serum vitamin D metabolome: What we know and what is still to discover

Tuckey

Cheng

Slominski

2019

The Journal of Steroid Biochemistry and Molecular Biology

186

178

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Vitamin D, referring to the two forms, D2 from the diet and D3 primarily derived from phototransformation in the skin, is a prohormone important in human health. The most hormonally active form, 1α,25-dihydroxyvitamin D (1α,25(OH)D), formed from vitamin D via 25-hydroxyvitamin D (25(OH)D), is not only important for regulating calcium metabolism, but has many pleiotropic effects including regulation of the immune system and has anti-cancer properties. The major circulating form of vitamin D is 25(OH)D and both D2 and D3 forms are routinely measured by LC/MS/MS to assess vitamin D status, due to their relatively long half-lives and much higher concentrations compared to 1α,25(OH)D. Inactivation of both 25(OH)D and 1α,25(OH)D is catalyzed by CYP24A1 and 25-hydroxyvitamin D3 3-epimerase. Initial products from these enzymes acting on 25(OH)D3 are 24R,25(OH)D3 and 3-epi-25(OH)D3, respectively, and both of these can also be measured routinely in some clinical laboratories to further document vitamin D status. With advances in LC/MS/MS and its increased availability, and with the help of studies with recombinant vitamin D-metabolizing enzymes, many other vitamin D metabolites have now been detected and in some cases quantitated, in human serum. CYP11A1 which catalyzes the first step in steroidogenesis, has been found to also act on vitamins D3 and D2 hydroxylating both at C20, but with some secondary metabolites produced by subsequent hydroxylations at other positions on the side chain. The major vitamin D3 metabolite, 20S-hydroxyvitamin D3 (20S(OH)D3), shows biological activity, often similar to 1α,25(OH)D3 but without calcemic effects. Using standards produced enzymatically by purified CYP11A1 and characterized by NMR, many of these new metabolites have been detected in human serum, with semi-quantitative measurement of 20S(OH)D3 indicating it is present at comparable concentrations to 24R,25(OH)D3 and 3-epi-25(OH)D3. Recently, vitamin D-related hydroxylumisterols derived from lumisterol3, a previtamin D3 photoproduct, have also been measured in human serum and displayed biological activity in initial in vitro studies. With the current extensive knowledge on the reactions and pathways of metabolism of vitamin D, especially those catalyzed by CYP24A1, CYP27A1, CYP27B1, CYP3A4 and CYP11A1, it is likely that many other of the resulting hydroxyvitamin D metabolites will be measured in human serum in the future, some contributing to a more detailed understanding of vitamin D status in health and disease.

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Section: (Oh)d2mentioning

confidence: 98%

The serum vitamin D metabolome: What we know and what is still to discover

Tuckey

Cheng

Slominski

2019

The Journal of Steroid Biochemistry and Molecular Biology

186

178

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“…Doxercalciferol ( 21 ), developed by Bone Care International, was launched in 1999 with the sales name of Hectorol for the treatment of 2HPT in the US. Although doxercalciferol ( 21 ) is a prodrug of active vitamin D 2 (1α,25-dihydroxyvitamin D 2 22 ) ( Scheme 4 ) and, like calcitriol (1α,25-dihydroxyvitamin D 3 ), which is the counterpart of alfacalcidol, must be activated in vivo , the mechanism for the biological action of doxercalciferol is much less well understood than for alfacalcidol [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. The results of a trial with doxercalciferol in renal failure patients with moderate to severe 2HPT (intact PTH greater than 400 pg/mL) were reported [ 33 ].…”

Section: Doxercalciferolmentioning

confidence: 99%

A New Look at the Most Successful Prodrugs for Active Vitamin D (D Hormone): Alfacalcidol and Doxercalciferol

Kubodera¹

2009

Molecules

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Alfacalcidol (1α-hydroxyvitamin D3) has been widely used since 1981 as a prodrug for calcitriol (1α,25-dihydroxyvitamin D3) in the treatment of hypocalcemia, chronic renal failure, hypoparathyroidism and osteoporosis. More recently, doxercalciferol (1α-hydroxyvitamin D2) has been used since 1999 as a prodrug for 1α,25-dihydroxyvitamin D2 for the treatment of secondary hyperparathyroidism. Currently, six forms of vitamin D are known. They range from vitamin D2 to vitamin D7 and are distinguished by their differing side chains. Only vitamin D2 and vitamin D3 have been found to be biologically active based on the elucidation of activation pathways. Alfacalcidol and osteoporosis/doxercalciferol and secondary hyperparathyroidism are discussed, with a new look at old compounds including their practical syntheses.

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“…Because of the structural differences in the side chains of vitamins D2 and D3, some of the aforementioned chemical alterations occurring on the side chain of 1,25-(OH)2D3 may not occur on the side chain of l,25(OH)2D2 especially with respect to C-23 hydroxylation, C-24 ketonization, and C-23:C-26 lactonization. As far as C-24 hydroxylation is concerned, it has been already well established that vitamin D2 and 25(OH)D2 undergo C-24 hydroxylation to form 24(OH)D2 and 24,25(OH)2D2, respectively (Jones et al, 1979(Jones et al, , 1980. Therefore, l,25(OH)2D2 may also undergo C-24 hydroxylation to form l,24,25(OH)3D2.…”

Section: Discussionmentioning

confidence: 99%

Isolation and identification of 1,24,25-trihydroxyvitamin D2, 1,24,25,28-tetrahydroxyvitamin D2, and 1,24,25,26-tetrahydroxyvitamin D2: new metabolites of 1,25-dihydroxyvitamin D2 produced in the rat kidney

Gs¹,

Ky²

1986

Biochemistry

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Three new metabolites of vitamin D2 were produced in vitro by perfusing isolated rat kidneys with 1,25-dihydroxyvitamin D2. They were isolated and purified from the kidney perfusate by the techniques of methanol-methylene chloride lipid extraction and high-performance liquid chromatography. By means of ultraviolet absorption spectrophotometry, mass spectrometry, and specific chemical reactions, the metabolites were identified as 1,24,25-trihydroxyvitamin D2, 1,24,25,28-tetrahydroxyvitamin D2, and 1,24,25,26-tetrahydroxyvitamin D2. Both 1,24,25,28-tetrahydroxyvitamin D2 and 1,24,25,26-tetrahydroxyvitamin D2 were also produced when a kidney was perfused with 1,24,25-trihydroxyvitamin D2. Thus, it becomes clear that 1,25-dihydroxyvitamin D2 is first hydroxylated at C-24 to form 1,24,25-trihydroxyvitamin D2, which is then further hydroxylated at C-28 and C-26 to form 1,24,25,28-tetrahydroxyvitamin D2 and 1,24,25,26-tetrahydroxyvitamin D2, respectively. From several recent studies, it has been well established that 1,25-dihydroxyvitamin D3 is converted into various further metabolites in the kidney as a result of chemical reactions such as C-23, C-24, and C-26 hydroxylations, C-24 ketonization, and C-23:C-26 lactonization. From our study it is obvious that 1,25-dihydroxyvitamin D2 does not undergo all of the aforementioned chemical reactions except C-24 and C-26 hydroxylations. Also, our study indicates that C-28 hydroxylation plays a significant role in the further metabolism of 1,25-dihydroxyvitamin D2. Thus, for the first time, we describe a novel further metabolic pathway for 1,25-dihydroxyvitamin D2 in a mammalian kidney.

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Isolation and identification of 24,25-dihydroxy vitamin D2 by use of the perfused rat kidney

Cited by 25 publications

References 16 publications

The serum vitamin D metabolome: What we know and what is still to discover

The serum vitamin D metabolome: What we know and what is still to discover

A New Look at the Most Successful Prodrugs for Active Vitamin D (D Hormone): Alfacalcidol and Doxercalciferol

Isolation and identification of 1,24,25-trihydroxyvitamin D2, 1,24,25,28-tetrahydroxyvitamin D2, and 1,24,25,26-tetrahydroxyvitamin D2: new metabolites of 1,25-dihydroxyvitamin D2 produced in the rat kidney

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