title: Metabolic activation of 1alpha-hydroxyvitamin D3 in human liver microsomes.
abstract: 1. 1Alpha-hydroxyvitamin D3 (1alpha-OH-D3) is a synthetic prodrug of the active form of vitamin D3, and requires the hydroxylation at the C-25 position before eliciting its biological activity. 2. 25-Hydroxylation activities for 1alpha-OH-D3 were present in both microsomal and mitochondrial fractions of human liver. 3. To determine the P450 enzyme(s) involved in microsomal 25-hydroxylation, 14 P450s (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val, 2D6-Met, 2E1, 3A4, 4A11) were tested for their 25-hydroxylation activity of 1alpha-OH-D3. None catalysed the 25-hydroxylation reaction. 4. 1Alpha-OH-D3 in a high concentration (2.5 ng ml(-1)) showed small but significant inhibition of the catalytic activities of CYP2C8, 2C9-Cys, 2C19, 2D6-Val and 2E1 for their typical substrates. However, 1alpha-OH-D3 in a clinically used low concentration will not significantly affect drug metabolism catalysed by the 14 P450s tested. 5. In summary, the 25-hydroxylation activity of 1alpha-OH-D3 that localizes in the microsomal fraction appears to be attributable to a cytochrome P450 other than the microsomal forms tested in this study.
authors.affiliation: Product Research Laboratory, Chugai Pharmaceutical Co. Ltd, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kamachi
authors.forename: K
authors.initials: K
authors.lastname: Sugimoto
authors.forename: T
authors.initials: T
authors.lastname: Yamasaki
authors.forename: N
authors.initials: N
authors.lastname: Hirose
authors.forename: H
authors.initials: H
authors.lastname: Ide
authors.forename: Y
authors.initials: Y
authors.lastname: Ohyama
mesh_terms: D001711:Biotransformation; D002112:Calcifediol / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D002112:Calcifediol