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Volume 270, Number 28, Issue of July 14, pp. 16766-16774, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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F. Jeffrey Dilworth , Ian Scott , Andrew Green , Stephen Strugnell , Yu-Ding Guo , Eve A. Roberts , Richard Kremer , Martin J. Calverley , Hugh L. J. Makin , Glenville Jones

A series of homologated 1-hydroxyvitamin D and 1,25-dihydroxyvitamin D molecules with one to three extra carbons in the side chain were used to examine the substrate preferences and hydroxylation site selection mechanisms of the liver vitamin D-25-hydroxylase (CYP27) and the target cell 25-hydroxyvitamin D-24-hydroxylase (CYP24). Cultured and transfected cell models, used as sources of these hydroxylases, gave 23-, 24-, 25-, and 27-hydroxylated metabolites which were identified by their high performance liquid chromatography and GC-MS characteristics. Lengthening the side chain is tolerated by each cytochrome P450 isoform such that 25-hydroxylation or 24-hydroxylation continues to occur at the same rate as in the native side chain, while the site of hydroxylation remains the same for the liver enzyme in that CYP27 continues to hydroxylate at C-25 and C-27 (minor) despite the two-carbon-atom extension. Somewhat surprising is the finding that C-24 and C-23 (minor) hydroxylations also do not change as the side chain is extended by as much as three carbons. We conclude that CYP24 must be directed to its hydroxylation site(s) by the distance of carbon 24 from the vitamin D ring structure and not as in CYP27 by the distance of the hydroxylation site from the end of the side chain.

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