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Michael A. Levine - One of the best experts on this subject based on the ideXlab platform.
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Decreased Serum 25-Hydroxyvitamin D in Aging Male Mice Is Associated With Reduced Hepatic CYP2R1 Abundance.
Endocrinology, 2018Co-Authors: Jeffrey D. Roizen, Alex Casella, Meizan Lai, Caela Long, Zahra Tara, Ilana Caplan, Lauren O’lear, Michael A. LevineAbstract:The prevalence of vitamin D deficiency, as determined by circulating levels of 25-hydroxycalciferol [25(OH)D], is greater in older individuals compared with the young. To examine the hypothesis that altered production or inactivation of 25(OH)D contributes to lower circulating levels of 25(OH)D, we measured the serum levels of parent vitamin D3 (cholecalciferol) and 25(OH)D. We also determined the relative abundance of transcripts encoding hepatic CYP2R1 and CYP27B1, the principal 25-hydroxylases, transcripts encoding enzymes that degrade 25(OH)D in the liver (Cyp3A11) and kidney (Cyp24A1) and transcripts encoding megalin and cubilin, proteins critical to vitamin D resorption in the kidney in mice at three different ages. We observed a significant decline in the relative abundance of CYP2R1 in the liver with aging (one-way ANOVA, P = 0.0077). Concurrent with the decrease in mRNA, a significant decline in hepatic CYP2R1 protein (one-way ANOVA for trend, P = 0.007) and 25(OH)D (one-way ANOVA for trend, P = 0.002) and in the ratio of 25(OH)D3 to cholecalciferol (one-way ANOVA, P = 0.0003). By contrast, levels of the transcripts encoding Cyp3a11, Cyp24a1, and Cyp27b1 megalin and cubilin were unchanged with aging. A significant positive correlation was found between CYP2R1 mRNA and 25(OH)D, and a stronger correlation was found between CYP2R1 mRNA and the ratio of 25(OH)D3 to cholecalciferol. These results indicate that decreased expression of CYP2R1 contributes to the reduced serum levels of 25(OH)D in aging.
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CYP2R1 mutations causing vitamin D-deficiency rickets.
The Journal of steroid biochemistry and molecular biology, 2016Co-Authors: Tom D. Thacher, Michael A. LevineAbstract:CYP2R1 is the principal hepatic 25-hydroxylase responsible for the hydroxylation of parent vitamin D to 25-hydroxyvitamin D [25(OH)D]. Serum concentrations of 25(OH)D reflect vitamin D status, because 25(OH)D is the major circulating metabolite of vitamin D. The 1α-hydroxylation of 25(OH)D in the kidney by CYP27B1 generates the fully active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D). The human CYP2R1 gene, located at 11p15.2, has five exons, coding for an enzyme with 501 amino acids. In CYP2R1-/- knockout mice, serum 25(OH)D levels were reduced by more than 50% compared wild-type mice. Genetic polymorphisms of CYP2R1 account for some of the individual variability of circulating 25(OH)D values in the population. We review the evidence that inactivating mutations in CYP2R1 can lead to a novel form of vitamin D-deficiency rickets resulting from impaired 25-hydroxylation of vitamin D. We sequenced the promoter, exons and intron-exon flanking regions of the CYP2R1 gene in members of 12 Nigerian families with rickets in more than one family member. We found missense mutations (L99P and K242N) in affected members of 2 of 12 families. The L99P mutation had previously been reported as a homozygous defect in an unrelated child of Nigerian origin with rickets. In silico analyses predicted impaired CYP2R1 folding or reduced interaction with substrate vitamin D by L99P and K242N mutations, respectively. In vitro studies of the mutant CYP2R1 proteins in HEK293 cells confirmed normal expression levels but completely absent or markedly reduced 25-hydroxylase activity by the L99P and K242N mutations, respectively. Heterozygous subjects had more moderate biochemical and clinical features of vitamin D deficiency than homozygous subjects. After an oral bolus dose of 50,000 IU of vitamin D2 or vitamin D3, heterozygous subjects had lower increases in serum 25(OH)D than control subjects, and homozygous subjects had minimal increases, supporting a semidominant inheritance of these mutations. No CYP2R1 mutations were found in 27 Nigerian children with sporadic rickets, a cohort of 50 unrelated Nigerian subjects, or in 628 unrelated subjects in the 1000 Genomes Project. We conclude that mutations in CYP2R1 are responsible for an atypical form of vitamin D-deficiency rickets, which has been classified as vitamin D dependent rickets type 1B (VDDR1B, MIM 600081).
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CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an atypical form of vitamin D deficiency
The Journal of clinical endocrinology and metabolism, 2015Co-Authors: Tom D. Thacher, Philip R. Fischer, Ravinder J. Singh, Jeffrey D. Roizen, Michael A. LevineAbstract:Context: Production of the active vitamin D hormone 1,25-dihydroxyvitamin D requires hepatic 25-hydroxylation of vitamin D. The CYP2R1 gene encodes the principal vitamin D 25-hydroxylase in humans. Objective: This study aimed to determine the prevalence of CYP2R1 mutations in Nigerian children with familial rickets and vitamin D deficiency and assess the functional effect on 25-hydroxylase activity. Design and Participants: We sequenced the CYP2R1 gene in subjects with sporadic rickets and affected subjects from families in which more than one member had rickets. Main Outcome Measures: Function of mutant CYP2R1 genes as assessed in vivo by serum 25-hydroxyvitamin D values after administration of vitamin D and in vitro by analysis of mutant forms of the CYP2R1. Results: CYP2R1 sequences were normal in 27 children with sporadic rickets, but missense mutations were identified in affected members of 2 of 12 families, a previously identified L99P, and a novel K242N. In silico analyses predicted that both subst...
Elizabeth Ramoslopez - One of the best experts on this subject based on the ideXlab platform.
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vitamin d hydroxylases CYP2R1 cyp27b1 and cyp24a1 in renal cell carcinoma
European Journal of Clinical Investigation, 2013Co-Authors: Anja Urbschat, Patrick Paulus, Quirine Freiin Von Quernheim, Patrick Bruck, Klaus Badenhoop, Stefan Zeuzem, Elizabeth RamoslopezAbstract:Background There is increasing evidence that vitamin D metabolites influence carcinogenesis. Besides its role in mineral homoeostasis, calcitriol, the active metabolite of vitamin D (1,25(OH)2D3), is known to possess antiproliferative, proapoptotic and immunomodulatory effects in cancer. Concerning the synthesis of vitamin D, the hydroxylases CYP2R1, CYP27B1 and CYP24A1 play a critical role, and the latter molecule determines the biological half-life of 1,25(OH)2D3, which is synthesized in the proximal renal tubules. Materials and methods The adjacency of these two biological processes prompted us to investigate the gene expression of CYP2R1, CYP27B1 and CYP24A1 in patients with ccRCC. Using RT-PCR, we retrospectively compared mRNA expression profiles from human ccRCC tumour samples with those derived from the corresponding adjacent healthy tissues (n = 30). Results We observed that all three genes (CYP2R1, CYP27B1 and CYP24A1) were upregulated in tumours compared with normal tissue (P < 0·0001). Moreover, CYP24A1 displayed a significantly higher expression in tumours than CYP27B1 (P < 0·05) and CYP2R1 (P < 0·0001), whereas no differences in the expression of these genes were found in healthy renal tissue. Gene expression of CYP2R1, CYP27B1 and CYP24A did not differ between pathological classifications (TNM, grading, presence of metastasis). Conclusion We thus conclude that upregulated gene expression of the catabolizing CYP24A1 as well as the synthesizing CYP2R1 and CYP27B1 may lead to a misbalance of vitamin D metabolites in ccRCC and thus contributing to its pathogenesis.
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abstract 4773 is upregulation of CYP2R1 cyp27b1 and cyp24 genes in clear cell renal cell carcinoma tissue involved in carcinogenesis
Cancer Research, 2013Co-Authors: Anja Urbschat, Patrick Paulus, Quirine Freiin Von Quernheim, Patrick Bruck, Elizabeth RamoslopezAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Renal cell carcinoma (RCC) represent approximately 3-5% of all malignancies reported each year. Among these clear cell renal cell carcinoma (ccRCC) represent the most frequently diagnosed histological classification accounting for 80% of renal cell carcinoma. The incidence has been reported to be higher in countries located at higher latitudes. In this context UVB-light which is essential for the synthesis of vitamin D has been inversely associated with the development of diverse carcinomas including renal cell carcinoma. Further steps of vitamin D synthesis are performed by CYP2R1, CYP27B1 and CYP24. We therefore investigated the quantitative mRNA expression of the CYP2R1, CYP27B1 and CYP24 genes in patients (n=29) with ccRCC. For this purpose total RNA was isolated from tumor and corresponding adjacent healthy tissues of all patients and integrity was assessed on a denaturing agarose gel stained with ethidium bromide. Intact RNA was transcribed using random hexameric primers and reverse transcriptase. Reverse transcription was performed and amplified by real-time PCR. Statistic association was evaluated by Mann-Whitney-Test and Kruskal-Wallis-Test. A P value less than 0.05 was considered significant. mRNA of all three genes (CYP2R1, CYP27B1 and CYP24) was expressed in both normal and carcinoma tissue with a significant upregulation in carcinoma tissue compared to normal tissue (p<0.0001). In tumor tissue CYP24 displayed a significantly higher expression than CYP27B1 or CYP2R1. Furthermore CYP27B1 showed a higher expression than CYP2R1 (p<0.0001). No differences in the expression of CYP2R1, CYP27B1 and CYP24 were found in normal renal tissue. We therefore conclude that differing gene expression of CYP2R1, CYP27B1 and CYP24 in normal- and carcinoma tissue could be involved in the pathogenesis of renal cell carcinoma. Citation Format: Anja E. Urbschat, Patrick Paulus, Quirine Freiin von Quernheim, Patrick Bruck, Elizabeth Ramos-Lopez. Is upregulation of CYP2R1-, CYP27B1- and CYP24 genes in clear cell renal cell carcinoma tissue involved in carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4773. doi:10.1158/1538-7445.AM2013-4773
Ashgan A. Alghobashy - One of the best experts on this subject based on the ideXlab platform.
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Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children.
Cellular immunology, 2012Co-Authors: Atef G. Hussein, Randa H. Mohamed, Ashgan A. AlghobashyAbstract:Abstract CYP2R1 (25α-hydroxylase) catalyzes vitamin D 3 to 25-hydroxyvitamin D 3 , while the CYP27B1 (1α-hydroxylase) catalyzes the 25(OH)D 3 to 1, 25(OH) 2 D 3 . 1, 25(OH) 2 D 3 prevents the development of autoimmune diabetes. We aimed to investigate CYP2R1 and CYP27B1 genes polymorphisms and susceptibility to type 1 diabetes in children. One hundred and twenty type 1 diabetic patients and One hundred and twenty controls were genotyped for CYP2R1 (rs10741657) and CYP27B1 (rs10877012) polymorphism. GG genotype of CYP2R1 increased risk to develop type 1 diabetes, and CC genotype of CYP27B1 increased risk to develop type 1 diabetes. Our finding suggested that GG genotype of CYP2R1 polymorphism and/or CC genotype of CYP27B1 polymorphism increased the risk of developing of type 1 diabetes in Egyptian children. In addition there was a synergism between GG genotype of CYP2R1 and CC genotype of CYP27B1 regarding the risk of development of type 1 diabetes.
Xinxin Ding - One of the best experts on this subject based on the ideXlab platform.
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human extrahepatic cytochromes p450 function in xenobiotic metabolism and tissue selective chemical toxicity in the respiratory and gastrointestinal tracts
Annual Review of Pharmacology and Toxicology, 2003Co-Authors: Xinxin Ding, Laurence S KaminskyAbstract:Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in the...
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human extrahepatic cytochromes p450 function in xenobiotic metabolism and tissue selective chemical toxicity in the respiratory and gastrointestinal tracts
Annual Review of Pharmacology and Toxicology, 2003Co-Authors: Xinxin Ding, Laurence S KaminskyAbstract:Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in these tissues, as well as future research needs, are discussed.
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biotransformation of coumarin by rodent and human cytochromes p 450 metabolic basis of tissue selective toxicity in olfactory mucosa of rats and mice
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Xiaoliang Zhuo, Xinxin Ding, Laurence S Kaminsky, Qingyu Zhang, David C SpinkAbstract:Coumarin was previously found to cause tissue-selective toxicity in the olfactory mucosa (OM) of rats and mice, with rats being the more sensitive species. The aim of this study was to explore the role of target tissue biotransformation in OM-selective toxicity and the metabolic basis of the species differences in coumarin toxicity. At least six coumarin metabolites were detected in OM microsomal reactions, with o-hydroxyphenylacetaldehyde (o-HPA) being the most abundant. Formation of o-HPA was inhibited by reduced glutathione, confirming its origin from a reactive intermediate. There were significant differences in the rates and metabolite profiles of coumarin metabolism in the livers of Wistar rats and C57BL/6 mice. The rates of metabolic activation of coumarin, as indicated by the formation of o-HPA, were comparable in OM microsomes of the two species but about 25- and 3-fold higher in OM than in liver microsomes of rats and mice, respectively. Thus, target tissue activation seems to play an important role in the tissue-selective toxicity, whereas differences in the rates of hepatic metabolism may be responsible for the species difference in olfactory toxicity. Purified, heterologously expressed mouse CYP2A5 and CYP2G1 produced 7-hydroxycoumarin and o-HPA as the predominant products, respectively. Kinetic analysis and immunoinhibition studies indicated that the OM-specific CYP2G1 plays the major role in metabolic activation of coumarin. Furthermore, of 13 human cytochrome P-450s (P-450s) examined, five (CYP1A1, CYP1A2, CYP2B6, CYP2E1, and CYP3A4) were active in the metabolic activation of coumarin, suggesting a potential risk of coumarin toxicity in humans.
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Role of CYP2A5 and 2G1 in Acetaminophen Metabolism and Toxicity in the Olfactory Mucosa of the Cyp1a2(−/−)Mouse
Biochemical pharmacology, 1998Co-Authors: Mary Beth Genter, Xinxin Ding, Hung-chi Liang, Masahiko Negishi, Ross A. Mckinnon, Daniel W. NebertAbstract:Acetaminophen (AP) is a widely-used analgesic agent that has been linked to human liver and kidney disease with prolonged or high-dose usage. In rodents, the target organs that are affected include liver, kidney, and the olfactory mucosa. AP toxicity requires cytochrome P450(CYP)-mediated metabolic activation, and the isozymes CYP1A2, 2E1, and 3A are known to activate AP in the human. In the present study, we determined that olfactory mucosal toxicity of AP was not different between the Cyp1a2(+/+) wild-type and the Cyp1a2(-/-) knockout mouse, whereas the hepatic toxicity of AP was significantly diminished in Cyp1a2(-/-) mice. Western blots of olfactory mucosa revealed that CYP2E1 and CYP3A levels are similar between untreated Cyp1a2(+/+) and Cyp1a2(-/-) mice. Diallyl sulfide (DAS), a known inhibitor of CYP2E1 and of CYP2A10/2A11 (the rabbit orthologue of mouse CYP2A5), completely eliminated olfactory toxicity of AP in both the Cyp1a2(-/-) and wild-type mouse olfactory mucosa. We found that heterologously expressed mouse CYP2A5 and CYP2G1 enzymes (known to be present in olfactory mucosa) form 3-hydroxyacetaminophen (3-OH-AP) and 3-(glutathion-S-yl)acetaminophen (GS-AP); CYP2A5 is considerably more active than 2G1. Addition of GSH caused increases in GS-AP proportional to decreases in 3-OH-AP, suggesting that these two metabolites arise from a common precursor or are formed by way of competing pathways. We also found that both CYP2A5 and CYP2G1 are inhibitable by DAS in vitro. These studies provide strong evidence that, in addition to CYP2E1, CYP2A5 and 2G1 are important in AP bioactivation in the mouse olfactory mucosa and that CYP1A2 appears to be of minor importance for AP olfactory toxicity.
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role of cyp2a5 and 2g1 in acetaminophen metabolism and toxicity in the olfactory mucosa of the cyp1a2 mouse
Biochemical Pharmacology, 1998Co-Authors: Mary Beth Genter, Xinxin Ding, Hung-chi Liang, Masahiko Negishi, Ross A. Mckinnon, Daniel W. NebertAbstract:Acetaminophen (AP) is a widely-used analgesic agent that has been linked to human liver and kidney disease with prolonged or high-dose usage. In rodents, the target organs that are affected include liver, kidney, and the olfactory mucosa. AP toxicity requires cytochrome P450(CYP)-mediated metabolic activation, and the isozymes CYP1A2, 2E1, and 3A are known to activate AP in the human. In the present study, we determined that olfactory mucosal toxicity of AP was not different between the Cyp1a2(+/+) wild-type and the Cyp1a2(-/-) knockout mouse, whereas the hepatic toxicity of AP was significantly diminished in Cyp1a2(-/-) mice. Western blots of olfactory mucosa revealed that CYP2E1 and CYP3A levels are similar between untreated Cyp1a2(+/+) and Cyp1a2(-/-) mice. Diallyl sulfide (DAS), a known inhibitor of CYP2E1 and of CYP2A10/2A11 (the rabbit orthologue of mouse CYP2A5), completely eliminated olfactory toxicity of AP in both the Cyp1a2(-/-) and wild-type mouse olfactory mucosa. We found that heterologously expressed mouse CYP2A5 and CYP2G1 enzymes (known to be present in olfactory mucosa) form 3-hydroxyacetaminophen (3-OH-AP) and 3-(glutathion-S-yl)acetaminophen (GS-AP); CYP2A5 is considerably more active than 2G1. Addition of GSH caused increases in GS-AP proportional to decreases in 3-OH-AP, suggesting that these two metabolites arise from a common precursor or are formed by way of competing pathways. We also found that both CYP2A5 and CYP2G1 are inhibitable by DAS in vitro. These studies provide strong evidence that, in addition to CYP2E1, CYP2A5 and 2G1 are important in AP bioactivation in the mouse olfactory mucosa and that CYP1A2 appears to be of minor importance for AP olfactory toxicity.
Kee Hyoung Lee - One of the best experts on this subject based on the ideXlab platform.
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Vitamin D level and gene polymorphisms in Korean children with type 1 diabetes.
Pediatric diabetes, 2019Co-Authors: Hyo-kyoung Nam, Young Jun Rhie, Kee Hyoung LeeAbstract:Background Vitamin D metabolism has been associated with type 1 diabetes. Objective We aimed to clarify the association of 25-hydroxylase (CYP2R1) and 1α-hydroxylase (CYP27B1) with risk of developing type 1 diabetes in Korean children. Methods In total, 252 children (96 type 1 diabetes and 156 healthy controls) under the age of 20 years were recruited. Serum 25-hydroxyvitamin D (25OHD) and 1α,25-dihydroxyvitamin D [1α,25(OH)2 D] levels were determined. Allelic, genotypic, and haplotypic distribution of CYP2R1 (rs12794714, rs10766196, rs10741657, rs2060793, and rs10766197) and CYP27B1 (rs4646536, rs10877012, and rs3782130) polymorphisms were determined. Clinical and biochemical data were analyzed according to genotype. Results Mean vitamin D level was considerably lower, and vitamin D deficiency was more prevalent in children with type 1 diabetes than in healthy controls. The GG genotype of CYP2R1 rs12794714 and AA genotype of CYP2R1 rs10766196 were significantly associated with risk of developing type 1 diabetes (odds ratio 2.00, 95% confidence interval 1.176-3.413 and odds ratio 1.88, 95% confidence interval 1.103-3.195, respectively). The GG+GA genotype of CYP2R1 rs12794714 and AA+AG genotype of CYP2R1 rs10766196 were associated with prevalent vitamin D deficiency in children with type 1 diabetes. These genotypes did not differ with respect to glycosylated hemoglobin and daily insulin requirement. Conclusions Serum 25OHD and 1α,25(OH)2 D levels were lower in children with type 1 diabetes than in healthy controls. CYP2R1 rs12794714 and rs10766196 polymorphisms were associated with a higher risk of type 1 diabetes. Thus, polymorphisms in vitamin D metabolism may contribute to susceptibility to type 1 diabetes in Korean children.
