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

The metabolism of eldecalcitol ( ED ‐71), a 2 β ‐hydroxypropoxylated analog of the active form of vitamin D 3 was investigated by using in vitro systems. ED ‐71 was metabolized to 1 α ,2 β ,25‐trihydroxyvitamin D 3 (1 α ,2 β ,25( OH ) 3 D 3 ) 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 CYP 1, 2, and 3 families, and revealed that CYP 3A4 had the activity. However, the CYP 3A4 ‐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 ( SC 4 MOL ) might contribute to the metabolism of ED ‐71. It is noted that SC 4 MOL is physiologically essential for cholesterol synthesis. Recombinant human SC 4 MOL expressed in COS 7, Saccharomyces cerevisiae , or Escherichia coli cells converted ED ‐71 to 1 α ,2 β ,25( OH ) 3 D 3 . Furthermore, we evaluated the metabolism of ED ‐71 by recombinant CYP 24A1, which plays an important role in the metabolism of the active form of vitamin D 3 (1 α ,25( OH ) 2 D 3 ) and its analogs. The k cat / K m value for 24‐ or 23‐hydroxylation of ED ‐71 was only 3% of that for 1 α ,25( OH ) 2 D 3 , indicating that ED ‐71 was resistant to CYP 24A1‐dependent catabolism. Among the three enzymes catalyzing ED ‐71, SC 4 MOL appears to be most important in the metabolism of ED ‐71. To the best of our knowledge, this is the first study showing that SC 4 MOL can function as a drug‐metabolizing enzyme. The yeast and E. coli expression systems for SC 4 MOL could be useful for structure‐function analyses of SC 4 MOL .