Cytochrome P450-mediated metabolism of vitamin D

Abstract

signal transduction system, the DBP-knockout mouse is normocalcemic and exhibits normal tissue distribution of vitamin D metabolites and vitamin D action despite exhibiting very low blood levels of 1,25-(OH) 2 D 3 . This unexpected phenotype raised questions about DBP's exact role: essential transporter or buffer against toxicity ( 7,8 ). Work performed on the 25-hydroxylases over the past four decades in humans and a variety of animal species has revealed that several cytochrome P450 enzymes 2 (CYP), such as CYP2R1, CYP27A1, CYP3A4, CYP2D25, and perhaps others, are capable of 25-hydroxylation of vitamin D 3 or related compounds. These CYPs can be referred to as vitamin D 3 -25-hydroxylases, and it is CYP2R1 that is emerging as the physiologically relevant enzyme ( 9 ). On the other hand, there is no ambiguity over the second step of 1 ␣ -hydroxylation or the 25-OH-D 3 -1 ␣ -hydroxylase enzyme responsible, which is carried by a single cytochrome P450 2 named CYP27B1 ( 10-12 ). The inactivation of vitamin D is carried out by the mitochondrial enzyme, 25-hydroxyvitamin D 3 -24-hydroxylase, fi rst described in the early 1970s and initially believed to be involved solely in the renal 24-hydroxylation of 25-OH-D 3 ( 13 ). Work performed over the last 35 years has shown that 24-hydroxylase enzyme activity is the result of CYP24A1 ( 5, 14 ). CYP24A1 catalyzes the conversion of both 25-OH-D 3 and 1,25-(OH) 2 D 3 into a series of 24-and 23-hydroxylated products targeted for excretion along well-established pathways culminating in the water-soluble biliary metabolite calcitroic acid or a 26,23-lactone.This article assembles the most currently pertinent literature on the activating and inactivating enzymes of vitamin D metabolism and highlights protein structure and enzymatic properties, crystal structures, gene organization, and The activation of vitamin D 3 is accomplished by sequential steps of 25-hydroxylation to produce the main circulating form, 25-hydroxyvitamin D (25-OH-D 3 ), followed by 1 ␣ -hydroxylation to the hormonal form, 1 ␣ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) ( 1 ) ( Fig. 1 ). The initial step of 25-hydroxylation occurs in the liver ( 2 ), and the second step occurs both in the kidney and extrarenal sites ( 3, 4 ). The fat-soluble vitamin D and its metabolites are transported from one tissue to another on the vitamin D-binding protein (DBP), which shows different affi nity for the individual metabolites ( 5 ). The cell-surface receptor megalin-cubilin is thought to facilitate the endocytosis of a DBP-bound 25-OH-D 3 into a number of cell types, especially kidney cells ( 6 ). While it is widely believed that DBP is an essential component of the vitamin D

Assessment of vitamin D status – a changing landscape

“…The primary catabolic pathway in humans commences with 24-hydroxylation and culminates in the formation of calcitroic acid, which is excreted in the bile. The mitochondrial P450 enzyme, CYP24A1, catalyzes the first step, and possibly some subsequent steps, of this pathway [44]. The preferred substrate for CYP24A1 is1,25-(OH) 2 D, but the enzyme is also active in metabolising 25-OHD to 24,25-(OH) 2 D [45,46].…”

“…In some instances, CYP24A1 enzyme activity may catalyze hydroxylation on carbon 23 rather than carbon 24 as the first catabolic step. In humans, this occurs at about 10% of the rate of 24-hydroxylation [44]. An initial 23-hydroxylation marks the vitamin D molecule for metabolism via a pathway which culminates in the production of 1,25-(OH) 2 D-26,23-lactone.…”

“…A vitamin D metabolite that has recently gained much attention is 24,25-OH 2 D, the major product of 25-OHD catabolism. The conversion of 25-OHD into 24,25-OH 2 D is catalyzed by the 24-hydroxylase enzyme (CYP24A1) [44]. Considering there is direct enzymatic conversion of 25-OHD into 24,25-OH 2 D it is not surprising that the concentrations of both compounds are strongly correlated [113].…”

Detection of 25-Hydroxyvitamin D3 with an Enzyme modified Electrode

“…Faulkner et al reported that Co(sep) 3+ can be used in a CYP4A1 system with rates comparable to those obtained with NADPH [26]. Another research group constructed a biosensor by immobilizing CYP3A4 and Co(sep) 3+ on a Nafion ® -modified electrode and reported relevant detection limits for the substrate of CYP3A4 [41].…”

“…Recent data suggest vitamin D may reduce the risk of cancers, heart disease, autoimmune diseases, and type-2 diabetes [23]. In addition, low vitamin D levels have been linked to neuropsychiatric disorders, such as depression [24], Parkinson's disease [25], and Alzheimer's disease [26].…”