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

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 k_cat/K_m 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.

DOI: 10.1002/prp2.120

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