ABSTRACT
In the last 10 years, there has been a remarkable renaissance in vitamin D research. Two key concepts have underpinned this renewed interest in the health benets of vitamin D. First is the continuing debate on the worldwide prevalence of vitamin D insufciency [1] and how optimal vitamin D status can be safely achieved through conventional exposure to sunlight and dietary intake [2]. Second is the potential for vitamin D to promote health benets beyond its classical effects on the skeleton [3-6]. Following a recent data review, the Institute of Medicine (IOM) has issued statements aimed at addressing some of the key questions concerning our new perspective on vitamin D and human health [7]. The Recommended Dietary Allowance of vitamin D for all age groups has been elevated based on bone responses to vitamin D. However, the IOM report also recognized the need for further research to better dene other “nonclassical” health benets of vitamin D. The latter reects the accumulation of recent data describing anticancer, immunomodulatory, angiogenic, and antihypertensive actions of vitamin D [3,5,8,9]. Central to this new perspective on vitamin D has been its proposed localized actions, with target cells expressing both the intracellular vitamin D receptor (VDR) and the enzyme
4.1 Introduction ............................................................................................................................99 4.2 Renal Expression of 1α-Hydroxylase and Classical Vitamin D Physiology ........................ 100 4.3 Extrarenal Synthesis of 1,25(OH)2D in Normal Physiology ................................................ 101
4.3.1 Skin ........................................................................................................................... 101 4.3.2 Immune System ........................................................................................................ 102 4.3.3 Placenta ..................................................................................................................... 103 4.3.4 Prostate and Breast ................................................................................................... 104 4.3.5 Bone .......................................................................................................................... 105 4.3.6 Endocrine Glands and Reproductive Tissues ........................................................... 105 4.3.7 GI Tract ..................................................................................................................... 106
4.4 Mechanisms for the Regulation of Extrarenal 1α-Hydroxylase ........................................... 107 4.4.1 Biochemistry and Regulation of Extrarenal 1α-Hydroxylase ................................... 107 4.4.2 CYP24A1 and Extrarenal Synthesis of 1,25(OH)2D ................................................ 109 4.4.3 Regulation of Monocyte 1α-Hydroxylase ................................................................. 110 4.4.4 Regulation of Extrarenal 1α-Hydroxylase in Cells Other than Macrophages .......... 111
4.5 Human Diseases Associated with Extrarenal Overproduction of 1,25(OH)2D .................... 112 4.5.1 Extrarenal 1α-Hydroxylase and Sarcoidosis ............................................................. 112 4.5.2 Extrarenal 1α-Hydroxylase in Other Granuloma-Forming Diseases ....................... 113 4.5.3 Extrarenal 1α-Hydroxylase, Malignant Lymphoproliferative Disorders, and
Autoimmune Disease ................................................................................................ 113 4.6 Summary and Conclusions ................................................................................................... 114 References ...................................................................................................................................... 115
that synthesizes the active form of vitamin D, i.e., 1,25-hydroxyvitamin D (1,25(OH)2D), from precursor 25-hydroxyvitamin D (25OHD). In classical vitamin D endocrinology, the vitamin activating enzyme 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase) is expressed predominantly in the kidneys, where it acts to support systemic levels of 1,25(OH)2D. However, in extrarenal tissues, the enzyme appears to act at a more localized level promoting nonclassical actions in a site-specic manner. In this setting, it is proposed that biological responses to vitamin D will be more dependent on the availability of substrate 25OHD for 1α-hydroxylase or, in other words, serum vitamin D status. Thus, extrarenal 1α-hydroxylase may be a pivotal factor in dening the impact of vitamin D on the broader features of human health. The following chapter compares the basic biochemistry and physiology of vitamin D metabolism in extrarenal tissues, with emphasis on the differential regulation of this enzyme relative to renal 1α-hydroxylase and the possible biological impact of the enzyme on diverse peripheral tissues.
