Therapeutic Potential of a Novel Vitamin D3 Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding

Abstract

The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D3 (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10−7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)2D3-mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D3 , the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT.

Vitamin D and Chronic Kidney Disease Association with Mineral and Bone Disorder: An Appraisal of Tangled Guidelines

“…Furthermore, the goal should not be complete normalization of iPTH levels. New developments, such as extended-release formulations [ 109 , 110 ] (which correct both vitamin D deficiency and are more effective than native in decreasing iPTH levels) and new analogs, biomarkers, molecular targets, and even renal pathologies [ 111 , 112 , 113 , 114 , 115 , 116 , 117 ], may then help us better define optimal VD and iPTH levels or the best formulation at different CKD stages [ 92 , 107 , 109 ], thereby directing us towards an improved, personalized medicine. It is possible that the approaches that we took to correct VD deficiency are at least partially wrong and that current interventions with native and/or active VD were not properly targeted at more effective goals.…”

SNPs in cytochrome P450 genes decide on the fate of individuals with genetic predisposition to Parkinson’s disease

“…CYP24A1 genetic polymorphisms were also shown to be significantly associated with the occurrence of an ischemic stroke (Yang et al, 2020). In this relation, it should be mentioned that overexpression of CYP24A1 could serve as a possible drug target as successful attempts for selective inhibition of CYP24A1 have already been made (Schuster et al, 2006;Alshabrawy et al, 2022). Due to the importance of CYP24A1 in vitamin D metabolism, we checked whether there is a difference in the manifestation of the disease in dependence on the intake of vitamin D as a supplement, since data for some individuals are available in the PPMI database.…”