Endocrinol Metab.  2022 Jun;37(3):392-407. 10.3803/EnM.2021.1349.

Interplay of Vitamin D and CYP3A4 Polymorphisms in Endocrine Disorders and Cancer

• Kasarla SS
• Garikapati V
• Kumar Y
• Dodoala S

• KMID: 2531383
• DOI: http://doi.org/10.3803/EnM.2021.1349

Abstract

Vitamin D has received considerable optimistic attention as a potentially important factor in many pathological states over the past few decades. However, the proportion of the active form of vitamin D metabolites responsible for biological activity is highly questionable in disease states due to flexible alterations in the enzymes responsible for their metabolism. For instance, CYP3A4 plays a crucial role in the biotransformation of vitamin D and other drug substances. Food-drug and/or drug-drug interactions, the disease state, genetic polymorphism, age, sex, diet, and environmental factors all influence CYP3A4 activity. Genetic polymorphisms in CYP450-encoding genes have received considerable attention in the past few decades due to their extensive impact on the pharmacokinetic and dynamic properties of drugs and endogenous substances. In this review, we focused on CYP3A4 polymorphisms and their interplay with vitamin D metabolism and summarized the role of vitamin D in calcium homeostasis, bone diseases, diabetes, cancer, other diseases, and drug substances. We also reviewed clinical observations pertaining to CYP3A4 polymorphisms among the aforementioned disease conditions. In addition, we highlighted the future perspectives of studying the pharmacogenetics of CYP3A4, which may have potential clinical significance for developing novel diagnostic genetic markers that will ascertain disease risk and progression.

Keyword

Cytochrome P-450 CYP3A; Vitamin D; Neoplasms; Bone diseases; Immune system; Diabetes mellitus; COVID-19; 25-Hydroxyvitamin D 3

Figure

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  Fig. 1. Metabolism of vitamin D. The biotransformation of vitamin D3 (from ultraviolet irradiation) and vitamin D2 (from food sources) is carried out by cytochrome P450 (CYP) enzymes. The active 1,25(OH)2D3 formed from various metabolic conversions, binds to the vitamin D receptors, followed by retinoid X receptor (RXR) dimerization, which results in the formation of vitamin D responsive genes eventuating the respective physiological activities. Furthermore, the hormonally active 1,25(OH)2D3 is maintained by the negative/positive feedback mechanism of parathyroid hormone (PTH) [6-11]. UVB, ultraviolet B; DBP, vitamin D binding proteins; VDR, vitamin D receptor; VDRE, vitamin D responsive elements; FGF, fibroblast growth factor; CV, cardiovascular.

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  Fig. 2. Vitamin D and its effects on calcium and skeletal homeostasis, focusing on the role of 1,25(OH)2D3. Calcium from the food sources is absorbed by transcellular transport by transient receptor potential cation channel subfamily V member 5/6 (TRPV5/6) channels into enterocytes, where it forms a calcium-calbindin complex. The formed calcium complex enters the blood circulation via paracellular and/or transcellular transport and is used for a wide range of physiological processes. Based on the increased or decreased levels of calcium, parathyroid hormone (PTH)/fibroblast growth factor-23 (FGF23) shows the following activities: stimulating or inhibiting 1,25(OH)2D3, which further promotes vitamin D receptor (VDR)-retinoid X receptor (RXR) dimerization leads to the expression of vitamin D-responsive genes, eliciting effects on calcium transport channels and maintaining an optimum calcium concentration in enterocytes as depicted; balancing bone resorption and calcification; and promoting the CYP27B1 enzyme, which eventually increases the formation of 1,25(OH)2D3 in the kidney [24,25,28,35,36]. ↑ indicates increase; ↓ indicates decrease. NCX1, sodium-calcium exchanger-1; PCMA, plasma membrane Ca2+ ATPase; RANKL, receptor activator of nuclear factor kappa-Β ligand.

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  Fig. 3. Physiological activities of hormonally active vitamin D. (A) The role of vitamin D in innate immunity. The entry of pathogens by pattern recognition receptors (PRRs) promotes the induction of vitamin D receptor (VDR) and forms 1,25(OH)2D3. The active form of vitamin D (1,25(OH)2D3) stimulates the expression of various genes, including cathelicidin antimicrobial peptide (CAMP), nucleotide-binding oligomerization domain-containing protein 2 (NOD2), hepcidin antimicrobial protein (HAMP), and β-defensin 4 (DEFB4), which aid in pathogen killing. It also blocks pathogen entry by inhibiting toll-like receptors 2/4 (TLR2/4), regulates the tight junctions of epithelial cells, promotes various activities (e.g., generation of reactive oxygen species [ROS], chemotaxis, and phagocytosis), and inhibits interleukins and maturation of dendritic cell migration/maturation, thereby controlling inflammation and the development of autoimmunity [42,47]. (B) The development of adaptive immunity by activating B-cells and regulating the activities of different kinds of T-cells [42,47]. (C) The physiological effects of 1,25(OH)2D3 on cancerous cells, pancreatic β-cells, and the cardiovascular system. 1,25(OH)2D3 also inhibits the imbalance of angiotensin-converting enzyme-II (ACE-II) and angiotensin-II (Ang-II) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which prevents pulmonary vasoconstriction and also improves the ability of the immune system to fight against the virus [81]. VDRE, vitamin D responsive elements; IL, interleukin; TGFβ, transforming growth factor beta; CCR10, chemokine receptor; Treg, regulatory T cells; TH, helper T cells; CVD, cardiovascular disease.

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