Metabolism of 2α-propoxy-1α,25-dihydroxyvitamin D3 and 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP27A1 and CYP24A1

Daisuke Abe, Toshiyuki Sakaki, Tatsuya Kusudo, Atsushi Kittaka, Nozomi Saito, Yoshitomo Suhara, Toshie Fujishima, Hiroaki Takayama, Hiromi Hamamoto, Masaki Kamakura, Miho Ohta, Kuniyo Inouye

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Recently, we demonstrated that some A-ring-modified vitamin D3 analogs had unique biological activity. Of these analogs, 2α-propoxy- 1α,25(OH)2D3 (C3O1) and 2α-(3-hydroxypropoxy)- 1α,25(OH)2D3 (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 Km and kcat values of human CYP24A1 for O2C3 are, respectively, approximately 16 times more and 3 times less than those for 1α,25(OH)2D3. Thus, the catalytic efficiency, kcat/Km, of human CYP24A1 for O2C3 is only 2% of 1α,25(OH)2D3. 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.

Original languageEnglish
Pages (from-to)778-784
Number of pages7
JournalDrug Metabolism and Disposition
Volume33
Issue number6
DOIs
Publication statusPublished - 2005 Jun
Externally publishedYes

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Metabolism
Rats
Metabolites
Oxidation
Calcitriol Receptors
Cholecalciferol
Bioactivity
Vitamin D3 24-Hydroxylase
2-(3-hydroxypropoxy)-1,25-dihydroxyvitamin D3
Animals
Chemical activation
Calcium
Kinetics
Experiments

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Metabolism of 2α-propoxy-1α,25-dihydroxyvitamin D3 and 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP27A1 and CYP24A1. / Abe, Daisuke; Sakaki, Toshiyuki; Kusudo, Tatsuya; Kittaka, Atsushi; Saito, Nozomi; Suhara, Yoshitomo; Fujishima, Toshie; Takayama, Hiroaki; Hamamoto, Hiromi; Kamakura, Masaki; Ohta, Miho; Inouye, Kuniyo.

In: Drug Metabolism and Disposition, Vol. 33, No. 6, 06.2005, p. 778-784.

Research output: Contribution to journalArticle

Abe, D, Sakaki, T, Kusudo, T, Kittaka, A, Saito, N, Suhara, Y, Fujishima, T, Takayama, H, Hamamoto, H, Kamakura, M, Ohta, M & Inouye, K 2005, 'Metabolism of 2α-propoxy-1α,25-dihydroxyvitamin D3 and 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP27A1 and CYP24A1', Drug Metabolism and Disposition, vol. 33, no. 6, pp. 778-784. https://doi.org/10.1124/dmd.104.003038
Abe, Daisuke ; Sakaki, Toshiyuki ; Kusudo, Tatsuya ; Kittaka, Atsushi ; Saito, Nozomi ; Suhara, Yoshitomo ; Fujishima, Toshie ; Takayama, Hiroaki ; Hamamoto, Hiromi ; Kamakura, Masaki ; Ohta, Miho ; Inouye, Kuniyo. / Metabolism of 2α-propoxy-1α,25-dihydroxyvitamin D3 and 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP27A1 and CYP24A1. In: Drug Metabolism and Disposition. 2005 ; Vol. 33, No. 6. pp. 778-784.
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abstract = "Recently, we demonstrated that some A-ring-modified vitamin D3 analogs had unique biological activity. Of these analogs, 2α-propoxy- 1α,25(OH)2D3 (C3O1) and 2α-(3-hydroxypropoxy)- 1α,25(OH)2D3 (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 Km and kcat values of human CYP24A1 for O2C3 are, respectively, approximately 16 times more and 3 times less than those for 1α,25(OH)2D3. Thus, the catalytic efficiency, kcat/Km, of human CYP24A1 for O2C3 is only 2{\%} of 1α,25(OH)2D3. 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.",
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T1 - Metabolism of 2α-propoxy-1α,25-dihydroxyvitamin D3 and 2α-(3-hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by human CYP27A1 and CYP24A1

AU - Abe, Daisuke

AU - Sakaki, Toshiyuki

AU - Kusudo, Tatsuya

AU - Kittaka, Atsushi

AU - Saito, Nozomi

AU - Suhara, Yoshitomo

AU - Fujishima, Toshie

AU - Takayama, Hiroaki

AU - Hamamoto, Hiromi

AU - Kamakura, Masaki

AU - Ohta, Miho

AU - Inouye, Kuniyo

PY - 2005/6

Y1 - 2005/6

N2 - Recently, we demonstrated that some A-ring-modified vitamin D3 analogs had unique biological activity. Of these analogs, 2α-propoxy- 1α,25(OH)2D3 (C3O1) and 2α-(3-hydroxypropoxy)- 1α,25(OH)2D3 (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 Km and kcat values of human CYP24A1 for O2C3 are, respectively, approximately 16 times more and 3 times less than those for 1α,25(OH)2D3. Thus, the catalytic efficiency, kcat/Km, of human CYP24A1 for O2C3 is only 2% of 1α,25(OH)2D3. 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.

AB - Recently, we demonstrated that some A-ring-modified vitamin D3 analogs had unique biological activity. Of these analogs, 2α-propoxy- 1α,25(OH)2D3 (C3O1) and 2α-(3-hydroxypropoxy)- 1α,25(OH)2D3 (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 Km and kcat values of human CYP24A1 for O2C3 are, respectively, approximately 16 times more and 3 times less than those for 1α,25(OH)2D3. Thus, the catalytic efficiency, kcat/Km, of human CYP24A1 for O2C3 is only 2% of 1α,25(OH)2D3. 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.

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