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Novel Pathways of CYP3A‐dependent Metabolism of 25‐Hydroxyvitamin D3
Author(s) -
Wang Zhican,
Senn Tauri,
Hashizume Takanori,
Lin Yvonne,
Thummel Kenneth
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.812.5
Vitamin D 3 is critical for the regulation of calcium and phosphate homeostasis. The major circulating form, 25‐hydroxyvitamin D 3 (25OHD 3 ), is converted to the biologically active form, 1α,25‐dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] in the kidney. Previously, we reported that cytochrome P450 3A4 (CYP3A4) was able to catalyze stereospecific metabolism of 1α,25(OH) 2 D 3 . We now demonstrate that CYP3A4 is a multi‐functional enzyme capable of hydroxylating the alkyl side chain and A‐ring of 25OHD 3 . Apart from CYP3A5, no other human microsomal P450 enzyme catalyzed these reactions. A total of nine metabolites have been identified in vitro : seven known metabolites [24R/S,25(OH) 2 D 3 ; 23R/S,25(OH) 2 D 3 ; 25,26(OH) 2 D 3 ; 1α,25(OH) 2 D 3 ; and 3‐epi‐25(OH) 2 D 3 ] and two major new metabolites. One of the new metabolites circulates in plasma at concentrations comparable to that of 1α,25(OH) 2 D 3 . In a pilot study (n=6), we observed that the levels of this new metabolite were increased significantly after multiple oral doses of rifampin, a potent CYP3A4 inducer. These in vitro and in vivo results clearly suggest a novel CYP3A‐dependent pathway of 25OHD 3 metabolism, which may be subjected to drug interactions.