Hydroxylase enzymes of the Vitamin D pathway: Expression, function, and regulation

Copyright © 2002 by Annual Reviews. All rights reservedVitamin D is a secosteroid that is metabolically activated and degraded through the actions of three cytochrome P450 hydroxylase enzymes. Bioactivation occurs through the sequential actions of cytochromes P450C25 and P450C1, resulting in synthesis of the pleiotropic hormone 1,25-dihydroxyvitamin D (1,25VD), which regulates over 60 genes whose actions include those associated with calcium homeostasis and immune responses as well as cellular growth, differentiation, and apoptosis. Inactivation of 1,25VD occurs by C23/C24 oxidation pathways that are catalyzed by the multifunctional cytochrome P450C24 enzyme. Both P450C1 and P450C24 are highly regulated enzymes whose differential expression is controlled in response to numerous cellular modulatory agents such as parathyroid hormone (PTH), calcitonin, interferon gamma, calcium, phosphorus, and pituitary hormones as well as the secosteroid hormone 1,25VD. Most thoroughly studied at the molecular level are the actions of PTH to upregulate P450C1 gene expression and 1,25VD to induce the expression of P450C24. The regulatory action of PTH is mediated through the protein kinase A pathway and involves the phosphorylation of transcription factors that function at the proximal promoter of the P450C1 gene. The upregulation of P450C24 by 1,25VD has both a rapid nongenomic and a slower genomic component that are functionally linked. The rapid response involves protein kinase C and mitogen-activated protein kinase (MAPK) pathways that direct the phosphorylation of nuclear transcription factors. The slower genomic actions are linked to the binding of 1,25VD to the vitamin D receptor (VDR) and the interaction of the VDR-1,25VD complex with its heterodimer partner retinoid-X-receptor and associated coactivators. The regulatory complex is assembled on vitamin D response elements in the proximal promoter of the P450C24 gene and functions to increase the transcription rate.John L. Omdahl, Howard A. Morris, and Brian K. Ma

Skin Disease in Mastocytosis

The hallmark of mastocytosis is the pathological accumulation of mast cells in various tissues. The skin is the most frequently affected organ, followed by bone marrow. Cutaneous mast cell infiltration is usually associated with typical skin lesions. According to the morphology of the lesions, three subforms are distinguished, namely maculopapular cutaneous mastocytosis, diffuse cutaneous mastocytosis and cutaneous mastocytoma. Maculopapular cutaneous mastocytosis is further subdivided into a monomorphic and a polymorphic variant. An important diagnostic feature of all subforms is a positive Darier’s sign. There are significant clinical differences in skin lesions based on the age of disease onset. Paediatric patients often show cutaneous mastocytoma or the polymorphic variant of maculopapular cutaneous mastocytosis, normally without systemic involvement, and a transient disease course with spontaneous remission after several years. By contrast, adults typically present with the monomorphic variant of maculopapular cutaneous mastocytosis, usually associated with systemic mastocytosis and a chronic or progressive course. Patients with skin lesions, regardless of whether bone marrow and other organs are involved, can experience mast cell mediator symptoms such as pruritus, anaphylaxis, flushing and diarrhoea. The current treatment mainly aims at reducing mediator symptoms using antihistamines and, if indicated, also adrenaline, corticosteroids, sodium cromoglycate, specific immunotherapy and omalizumab. Preliminary study results indicate that specific tyrosine kinase inhibitors will soon also become relevant in the treatment of skin involvement in mastocytosis