Human hepatic metabolism of the anti‐osteoporosis drug eldecalcitol involves sterol C4‐methyl oxidase

• Published in: Pharmacology research & perspectives Vol. 3; no. 2; pp. e00120 - n/a
• Main Authors: Yasuda, Kaori, Iwanaga, Yuasa, Ogawa, Kazuaki, Mano, Hiroki, Ueno, Sera, Kimoto, Shutaro, Ohta, Miho, Kamakura, Masaki, Ikushiro, Shinichi, Sakaki, Toshiyuki
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2015; BlackWell Publishing Ltd
• Subjects: Anti‐osteoporosis; Bone density; Cholesterol; CYP24A1; Cytochrome; cytochrome P450; Dehydrogenases; E coli; eldecalcitol; Enzymes; Liver; Metabolism; Metabolites; Original; Osteoporosis; Pharmaceuticals; Pharmacology; Prescription drugs; sterol C4‐methyl oxidase; Sterols; Studies; Vitamin D; Japan; CYP24A1; cytochrome P450; sterol C4-methyl oxidase; vitamin D; Anti-osteoporosis; eldecalcitol
• ISSN: 2052-1707; 2052-1707
• DOI: 10.1002/prp2.120

The metabolism of eldecalcitol (ED‐71), a 2β‐hydroxypropoxylated analog of the active form of vitamin D3 was investigated by using in vitro systems. ED‐71 was metabolized to 1α,2β,25‐trihydroxyvitamin D3 (1α,2β,25(OH)3D3) in human small intestine and liver microsomes. To identify the enzymes involved in this metabolism, we examined NADPH‐dependent metabolism by recombinant P450 isoforms belonging to the CYP1, 2, and 3 families, and revealed that CYP3A4 had the activity. However, the CYP3A4 ‐specific inhibitor, ketoconazole, decreased the activity in human liver microsomes by only 36%, suggesting that other enzymes could be involved in ED‐71 metabolism. Because metabolism was dramatically inhibited by cyanide, we assumed that sterol C4‐methyl oxidase like gene product (SC4MOL) might contribute to the metabolism of ED‐71. It is noted that SC4MOL is physiologically essential for cholesterol synthesis. Recombinant human SC4MOL expressed in COS7, Saccharomyces cerevisiae, or Escherichia coli cells converted ED‐71 to 1α,2β,25(OH)3D3. Furthermore, we evaluated the metabolism of ED‐71 by recombinant CYP24A1, which plays an important role in the metabolism of the active form of vitamin D3 (1α,25(OH)2D3) and its analogs. The kcat/Km value for 24‐ or 23‐hydroxylation of ED‐71 was only 3% of that for 1α,25(OH)2D3, indicating that ED‐71 was resistant to CYP24A1‐dependent catabolism. Among the three enzymes catalyzing ED‐71, SC4MOL appears to be most important in the metabolism of ED‐71. To the best of our knowledge, this is the first study showing that SC4MOL can function as a drug‐metabolizing enzyme. The yeast and E. coli expression systems for SC4MOL could be useful for structure‐function analyses of SC4MOL. e00120