C-25 hydroxylation of 1alpha,24(R)-dihydroxyvitamin D3 is catalyzed by 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1): metabolism studies with human keratinocytes and rat recombinant CYP24A1.

Recently, 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) has been shown to catalyze not only hydroxylation at C-24 but also hydroxylations at C-23 and C-26 of the secosteroid hormone 1alpha, 25-dihydroxyvitamin D3 (1alpha,25(OH)2D3). It remains to be determined whether CYP24A1 has the ability to hydroxylate vitamin D3 compounds at C-25. 1alpha,24(R)-dihydroxyvitamin D3 (1alpha,24(R)(OH)2D3) is a non-25-hydroxylated synthetic vitamin D3 analog that is presently being used as an antipsoriatic drug.

Tissue specific metabolism of 1alpha,25-dihydroxy-20-epi-vitamin D3 into new metabolites with significant biological activity: studies in rat osteosarcoma cells (UMR 106 and ROS 17/2.8).

In a recent study, we investigated the metabolism of 1alpha,25-dihydroxy-20-epi-vitamin D3 (1alpha,25(OH)2-20-epi-D3), a potent synthetic vitamin D3 analog in the isolated perfused rat kidney and proposed that the enhanced biological activity of 1alpha,25(OH)2-20-epi-D3 is in part due to its metabolism into stable bioactive intermediary metabolites derived via the C-24 oxidation pathway (Siu-Caldera et al. [1999] J. Steroid.

1alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 and 1alpha,25-dihydroxy-16-ene-23-yne-20-epi-vitamin D3: analogs of 1alpha,25-dihydroxyvitamin D3 that resist metabolism through the C-24 oxidation pathway are metabolized through the C-3 epimerization pathway.

The secosteroid hormone 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] is metabolized in its target tissues through modifications of both the side chain and the A-ring. The C-24 oxidation pathway, the previously well established main side chain modification pathway, is initiated by hydroxylation at C-24 of the side chain. The C-3 epimerization pathway, the newly discovered A-ring modification pathway, is initiated by epimerization of the hydroxyl group at C-3 of the A-ring.

Selective inhibitors of CYP24: mechanistic tools to explore vitamin D metabolism in human keratinocytes.

Human keratinocytes are fully competent cells of the vitamin D (VD) hormone system. They have the capacity to generate VD, to convert it to hormonally active 1alpha,25(OH)(2)D(3) and subsequently, to metabolize the hormone by self-induced CYP24. These reactions generate a cascade of highly transient products and, eventually terminate biologic activity.

Skin is an autonomous organ in synthesis, two-step activation and degradation of vitamin D(3): CYP27 in epidermis completes the set of essential vitamin D(3)-hydroxylases.

The current understanding of the vitamin D(3) system shows skin as the unique site of vitamin D(3) production and liver is thought to be the main site of conversion to 25(OH)D(3). Skin is capable of activating 25(OH)D(3) via 1alpha-hydroxylation and the resulting 1alpha,25(OH)(2)D(3) plays a role in epidermal homeostasis in normal and diseased skin. It also rapidly up-regulates the major vitamin D(3) metabolizing enzyme 24-hydroxylase at the mRNA level, which is an established indicator for 1alpha,25(OH)(2)D(3)-presence.

1alpha,25-Dihydroxy-3-epi-vitamin D3 a physiological metabolite of 1alpha,25-dihydroxyvitamin D3: its production and metabolism in primary human keratinocytes.

Recent studies of metabolism using pharmacological substrate concentrations of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)(2)D3] in several tissues including primary cultures of human keratinocytes, bovine parathyroid cells and bone cells led to the identification of 1alpha,25-dihydroxy-3-epi-vitamin D3 [1alpha,25(OH)(2)-3-epi-D3] as a major natural metabolite of 1alpha,25(OH)(2)D3. In the present study, we demonstrate that human keratinocytes incubated with 25-hydroxy[26,27-(3)H] vitamin D3 produce 1alpha,25(OH)(2)-3-epi-D3 along with 1alpha,25(OH)(2)D3. The production of 1alpha,25(OH)(2)-3-epi-D3 is also identified in human keratinocytes incubated with physiological substrate concentrations of 1alpha,25(OH)(2)D3.