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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The CYP2R1 gene maps to chromosome 11p15.2 (Cheng et al. 2003). It contains five exons and spans approximately 15.5 kb. The gene encodes a 501–amino acid protein with a molecular weight of 57 kDa. CYP2R1 (also known as vitamin D 25-hydroxylase) is mainly found in the liver, converting vitamin D into 25-hydroxyvitamin D (calcidiol), which is the major circulatory form of the vitamin (Cheng et al. 2004; Jones et al. 2014; Zhu et al. 2013). Calcidiol is subsequently converted by CYP27B1 (i.e., 25-hydroxyvitamin D3 1-α-hydroxylase) to calcitriol, the active form of vitamin D3 that binds to VDR, which mediates most of the physiological actions of the vitamin (Bikle 2014). Mitochondrial CYP27A1 is regarded as a physiologically important vitamin D3 25-hydroxylase, but CYP2R1 is thought to play a major role because of the absence of sex and species differences and catalytic activity toward both vitamin D2 and D3 (Zhu et al. 2013). CYP2R1 is regiospecific to the C25-position of a secosteroid in contrast to other CYP enzymes with vitamin D 25-hydroxylase activity (e.g., CYP27A1, 2C11, and 3A4). Indeed, there is a clear difference between CYP2R1 and 27A1 in the metabolism of vitamin D (Shinkyo et al. 2004). CYP2R1 shows hydroxylase activity at the C25-position, whereas CYP27A1 has hydroxylase activity at the C24- and C27-positions. CYP2R1 also shows significantly higher affinity and C25 hydroxylation activity toward vitamin D3 than CYP27A1 (Shinkyo et al. 2004).
Nutrigenomics for Sport and Exercise Performance
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Nanci S. Guest, Marc Sicova, Ahmed El-Sohemy
Vitamin D 25-hydroxylase is the key enzyme that activates vitamin D from its pre-formed type, which is obtained through sun exposure and the diet (9, 76). This enzyme is encoded by the CYP2R1 gene, and a variant of this gene has been associated with an increased risk of low circulating levels of vitamin D (139, 147). The GC gene encodes the vitamin D-binding protein, which binds vitamin D and transports it to tissues. A variant in this gene has also been associated with an increased risk of low circulating levels of vitamin D. In one study, individuals with the GG or GA genotype of CYP2R1 were nearly four times more likely to have insufficient vitamin D levels compared to those with the AA genotype after vitamin D supplementation (139). Those with the GG genotype of the GC gene were significantly more likely to have low vitamin D levels compared to those with the TT genotype. These results were consistent with findings from previous research, including the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT), which found significance on a genome-wide basis in 15 cohorts with over 30,000 participants for three genetic variants, including CYP2R1 (rs10741657) and GC (rs2282679), and vitamin D status (139, 147). Those with the risk variants may not efficiently absorb calcium, increasing their risk for stress and other bone fractures (53). Athletes who engage in weight-bearing repetitive-load sports, such as long-distance running, must monitor their vitamin D and calcium intake to decrease their risk of stress and other bone fractures (48, 91, 111).
Impact of DNA methylation on ADME gene expression, drug disposition, and efficacy
Published in Drug Metabolism Reviews, 2022
Xu Hao, Yuanyuan Li, Jialu Bian, Ying Zhang, Shiyu He, Feng Yu, Yufei Feng, Lin Huang
Vitamin D is the basic medicine for the treatment of osteoporosis, and its preparations mainly include ordinary vitamin D and calcitriol. Vitamin D is metabolized to 25(OH)D in the liver by CYP2R1 and CYP27A1. Then, in the kidney and other tissues, 25(OH)D is activated to calcitriol. Both 25(OH)D and calcitriol are metabolically inactivated by CYP24A1(CYP24) (Zhou et al. 2014). Zhou et al. verified that the baseline DNA methylation levels at eight CpG sites of CYP2R1 were negatively associated with 12-month increases in serum 25(OH)D, and the baseline DNA methylation levels at two CpG sites of CYP24A1 were also negatively associated with vitamin D response variation (Zhou et al. 2014). Novakovic et al. revealed that CYP24A1 gene was methylated in human placenta, purified cytotrophoblasts, and primary and cultured chorionic villus sampling tissue. And CYP24A1 promoter methylation down-regulated gene expression and abolished vitamin D mediated feedback activation, which played an important role in maximizing active vitamin D bioavailability at the fetal-maternal interface (Novakovic et al. 2009). The above two studies found a consistent correlation between CYP24A1 promoter methylation and the effects of vitamin D. Wjst et al. reported that there seemed to be also a tendency for higher MRs of CYP27B1 with lower 25-OH-D3 serum values (Wjst et al. 2010).
Genetic polymorphisms of vitamin D3 metabolizing CYP24A1 and CYP2R1 enzymes in Turkish patients with ischemic stroke
Published in Neurological Research, 2018
Aysun Türkanoğlu Özçelik, Tuğçe Öner, Birsen Can Demirdöğen, Vedat Semai Bek, Şeref Demirkaya, Orhan Adalı
Some researchers reported that vitamin D deficiency triggers hypertension, heart attack, diabetes, and atherosclerosis [2,12,13]. With all these evidence, vitamin D deficiency is appearing as a risk factor for stroke among the other risk factors like hypertension, smoking, hyperlipidemia, obesity, age, and gender. CYP24A1 and CYP2R1, important cytochrome P450 enzymes, expressed in the kidney and liver, respectively, are known to take role in vitamin D metabolism. CYP2R1 takes role in the biological activation process of vitamin D; on the other hand, CYP24A1 carries out the degradation of vitamin D [14]. Genetic variation in the genes which express CYP24A1 and CYP2R1 enzymes can change the enzyme activity in the organism. So, concentration of vitamin D can vary depending on the effect of these variations on the gene. The level of vitamin D has been reported as an important parameter for stroke risk and severity [12,15].
Vitamin D receptor gene polymorphism and vitamin D supplementation on clinical/ treatment outcome in tuberculosis: current and future perspectives
Published in Expert Review of Anti-infective Therapy, 2022
Sonal Sekhar Miraj, Navya Vyas, Shilia Jacob Kurian, Tejaswini Baral, Levin Thomas, B Shrikar Reddy, Murali Munisamy, Mithu Banerjee, Mahadev Rao
Several gene polymorphisms involved in the vitamin D pathway such as GC (rs16846876, rs7041, rs17467825, rs3755967, rs2282679, rs4588, rs1155563, and rs2298850), CYP3A4 (rs2242480), CYP24A1 (rs2209314), and NADSYN1/DHCR7 (rs3794060, rs7944926, rs12785878, and rs4944957) were reported to significantly affect the vitamin D levels [51]. Jolliffe et al. identified genetic polymorphisms in DBP, CYP2R1, and DHCR7 as the most frequently reported to be associated with the levels of vitamin D [52]. A meta-analysis report has evidenced the role of rs10741657 polymorphism in the CYP2R1 gene (encodes for the 25-hydroxylase in the vitamin D metabolism pathway) to be associated with the vitamin D levels as well as VDD [53]. SNP analysis of vitamin D pathway genes can also identify population groups who may require higher doses of vitamin D supplementation. CYP27B1 polymorphisms were reported to influence the response rate to vitamin D3 supplementation, with patients with rs10877012 G/T allele having a better response [54]. SNPs in the vitamin D pathway, such as in CYP24A1 (rs927650) and CYP27B1 (rs4646536) have also been reported to increase plasma concentration of rifampicin [55,56]. Hence, future research assessing the role of vitamin D supplementations in vitamin D levels as well as their influence on antitubercular drug concentrations in TB patients with these genetic polymorphisms is highly significant. Such studies can provide a clearer pragmatic picture of the interplay between vitamin D pathway polymorphisms, vitamin D levels, antitubercular drug concentration, as well as TB treatment outcomes.