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

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 <i>CYP3A4</i> 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 <i>CYP3A4</i> polymorphisms among the aforementioned disease conditions. In addition, we highlighted the future perspectives of studying the pharmacogenetics of <i>CYP3A4</i>, which may have potential clinical significance for developing novel diagnostic genetic markers that will ascertain disease risk and progression.

Revealing the association between vitamin D metabolic pathway gene variants and lung cancer risk: a systematic review and meta-analysis

“…Additionally, it activates 23R- and 24S-mediated conversion of 1α,25(OH)2D3 into inactive 1α,23R,25(OH) 2 D 3 and 1α,24S,25(OH) 2 D 3 ( Jones et al, 2014 ). Thus, CYP3A4 was extensively studied in the metabolism of vitamin D ( Wang et al, 2012 ; Piotrowska et al, 2019 ; Kasarla et al, 2022a ). Nevertheless, vitamin D inactivation is mainly dependent on CYP3A4 , and the cytochrome P450 3A5 enzyme encoded by the CYP3A5 gene catalyzes 23- or 24-hydroxylation of 1,25-(OH) 2 D 3 ( Xu et al, 2006 ; Klyushova et al, 2022 ).…”

“…In fact, it has been suggested that alterations in the vitamin D metabolism result mainly from the induction of hepatic P450 enzymes, including CYP3A4 and CYP24A1 ( Wang et al, 2013 ). Furthermore, in the case of vitamin D toxicity, the liver microsomal enzymes CYP3A4 and CYP3A5 and the extrarenal enzyme CYP24A1 promote the hydroxylation of vitamin D3 into inactive metabolites ( Klyushova et al, 2022 ; Kasarla et al, 2022b ). Vitamin D-binding proteins encoded by the GC gene transport the active metabolite 1.25- (OH)2D3 to target tissues where it can bind to the vitamin D receptor gene VDR and regulate physiological genes ( Kasarla et al, 2022b ).…”