Disease relevance of Cyp24a1

• A study was conducted to evaluate the immunogenicity of the Brucella melitensis ribosome recycling factor (RRF)-homologous protein (CP24) [1].
• The CP24 gene was cloned, expressed in Escherichia coli and purified [1].

High impact information on Cyp24a1

• FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h [2].
• Previous studies have suggested that both plasma 24,25-dihydroxyvitamin D [24,25-(OH)2D] concentrations and renal 25-hydroxyvitamin D-24-hydroxylase activity are increased in mice with X-linked hypophosphatemia (Hyp mice) [3].
• Based upon in vitro experiments, keratinocytes from Cyp24a1-null mice fail to synthesize [1beta-3H]calcitroic acid from [1beta-3H]1alpha,25(OH2D3 or [26,27-methyl-3H]24,25(OH)2D3 from [26,27-methyl-3H]25(OH)D3 as do control mice, confirming the target cell catabolic role of CYP24A1 in these processes [4].
• Cyp24a1-null mice showed difficulty in eliminating [1beta-3H]1alpha,25(OH)2D3 from the bloodstream and tissues over a 96-h time course, whereas heterozygotic mice eliminated the hormone within 6-12 h, although there was clearance of labeled hormone into water-soluble products involving liver in both genotypes [4].
• Altered pharmacokinetics of 1alpha,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 in the blood and tissues of the 25-hydroxyvitamin D-24-hydroxylase (Cyp24a1) null mouse [4].

Biological context of Cyp24a1

• This phenotype was rescued by crossing the 24-OHase mutant mice to mice harboring a targeted mutation in the vitamin D receptor gene, confirming that the elevated 1,25(OH)2D levels, acting through the vitamin D receptor, were responsible for the observed accumulation of osteoid [5].
• Our results confirm the physiological importance of the 24-OHase enzyme for maintaining vitamin D homeostasis, and they reveal that 24,25-dihydroxyvitamin D is a dispensable metabolite during bone development [5].
• Surprisingly, complete absence of 24-OHase activity during development leads to impaired intramembranous bone mineralization [5].
• The addition of dibutyryl cAMP (dbc AMP) to activin A-treated MEL cells dose-dependently attenuated 1,25(OH)2D3-mediated induction of 24-OHase activity, finally to a level comparable to that of the untreated cells at the final concentration of 100 nM dbcAMP, while dbcAMP itself by 100 nM did not affect MEL cell differentiation by 24 h [6].
• A cDNA encoding a 25-hydroxyvitamin D-3 24-hydroxylase, Cyp-24, has been isolated from mouse kidney cDNA library by hybridization screening [7].

Anatomical context of Cyp24a1

• Similarly, 1,25-(OH)2D3-induced increases in both 24-OHase mRNA and activity were apparent in the duodenum [8].
• Northern blot analysis of tissues from mice injected with 1,25-(OH)2D3 (24 pmol/g) revealed that the 3.4-kb 24-OHase messenger RNA (mRNA) is most abundant in kidney and intestine, with smaller amounts present in skin, thymus, and bone [8].
• RT-PCR and Southern blot analysis detected 24-OHase mRNA in several other tissues including lung, testis, spleen, pancreas, and heart [8].
• ST-630 was more effective than 1, 25-dihydroxyvitamin D3 [1,25(OH)2D3] with respect to the induction of Cyp24 and calbindin-D9k mRNAs in the kidney and in the small intestine [9].
• In addition, we studied 25-hydroxyvitamin D 24-hydroxylase activity in cultured pig kidney cells (LLC-PK1) to assess a mitochondrial P-450 enzyme in another organ [10].

Associations of Cyp24a1 with chemical compounds

• The 25-hydroxyvitamin D-24-hydroxylase enzyme (24-OHase) is responsible for the catabolic breakdown of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form of vitamin D. The 24-OHase enzyme can also act on the 25-hydroxyvitamin D substrate to generate 24,25-dihydroxyvitamin D, a metabolite whose physiological importance remains unclear [5].
• Although 1,25-(OH)2D3 increased the amount of 24-OHase mRNA in skin, enzyme activity was not detected in this tissue [8].
• These Gemini compounds also potently stimulate 25-hydroxyvitamin D 24-hydroxylase expression in As4.1-hVDR cells [11].
• These results indicate that ST-630 was more effective in inducing Cyp24 and calbindin-D9k gene expression than 1, 25(OH)2D3 when both compounds were injected into vitamin-D-deficient mice [9].

Regulatory relationships of Cyp24a1

• The present study was undertaken to evaluate the response of Hyp mice to regulators known to inhibit renal 25-hydroxyvitamin D3-1-hydroxylase (1-hydroxylase) and stimulate renal 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) [12].

Other interactions of Cyp24a1

• Both OCT and 1,25(OH)2D3 at 24 pmol/g body wt (i.p.) induced a single, 3.4-kb mRNA encoding vitamin D 24-hydroxylase (24-OHase), the cytochrome P450 enzyme responsible for 1,25(OH)2D3 degradation, in kidney and duodenum [13].

Analytical, diagnostic and therapeutic context of Cyp24a1

• RT-PCR showed that Cyp24a1-null mice have decreased expression of 25-hydroxyvitamin D-1alpha-hydroxylase that must play a role in their survival [4].
• Intraperitoneal injection of 1,25-(OH)2D3 induced dose- and time-dependent increases in both 24-OHase mRNA abundance and enzyme activity in mouse kidney [8].
• In this study we examined the expression of 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase) and 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) by RT-PCR and whole mount in situ hybridization using organ culture of kidney taken from mouse embryo [14].
• Molecular cloning of 25-hydroxyvitamin D-3 24-hydroxylase (Cyp-24) from mouse kidney: its inducibility by vitamin D-3 [7].
• However, the potential of CP24 for a Brucella diagnostic test based on an in vitro antigen (Ag)-specific IFN-gamma production or DTH test would be worth testing [1].

References