Nutrient Metabolism and Fetal Brain Development
Emilio Herrera, Robert H. Knopp in Perinatal Biochemistry, 2020
Despite these mechanisms for sparing carbohydrate, amino acid, and nitrogen, fetal brain growth is retarded during maternal starvation. One potentially contributing factor is that in fetal rat brain slices, ketone bodies interfere with the de novo pathway for purines and pyrimidines.19,20 In the de novo pathway of pyrimidine biosynthesis, β-hydroxybutyrate and acetoacetate inhibit the formation of orotic acid, but do not affect the conversion of orotic acid to uridine monophosphate.20 This highly specific effect is concentration dependent. During maternal starvation in late gestation, a 35% reduction in the formation of uridine monophosphate is seen in the rat. Modest elevations of ketone bodies as seen in human sera from mothers fasted for 18 h,20 reduced formation of uridine monophosphate by 10%.20 Ketone inhibition is limited to the de novo pathways for purine and pyrimidine biosynthesis. The salvage pathways for both purines and pyrimidines are unaffected.19 Since the salvage pathways are utilized in late gestation and neonatal life, the effects of ketone bodies on proliferative growth are limited to the time of intrauterine development.
Orotic aciduria
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The conceptualization of effective replacement therapy began with the first publication [1]. Administration of uridylic and cytidylic acids led to reduction in orotic acid excretion. This was presumably a consequence of breakdown in the intestine to uridine and cytidine, as oral bioavailability of nucleotides is very low, and their administration usually results in diarrhea. Uridine therapy was initiated by Becroft and Phillips in the second patient [2]. Treatment begun at 16 months with 1.5 g/day led to a prompt rise in hemoglobin and a normal bone marrow. Activity and interest in his surroundings improved immediately, as did appetite. Hair and nails began to grow, as did he, crossing percentile lines for weight from below the 3rd percentile to between the 90th and 97th percentile. He remained mildly mentally impaired, but there was no progression. It was interesting that he experienced a prompt relapse on substitution of uracil for uridine, even though the content of pyrimidine base was twice that of uridine, which at that time was 75 mg/kg. Uridine therapy is dependent for bioavailability on efficient intestinal absorption and the activity of the salvage enzyme uridine kinase (EC2.7.1.48) which leads directly to the formation of the nucleotide UMP [25, 26].
Transient Erythroblastopenia of Childhood
Stephen A. Feig, Melvin H. Freedman in Clinical Disorders and Experimental Models of Erythropoietic Failure, 2019
These unusual disorders of childhood are due to abnormalities in folate, vitamin B12, or pyrimidine (i.e. orotic acid) metabolism. Characteristically, these disorders present in young children. From a hematologic perspective, there is anemia and reticulocytopenia. However, in contrast to TEC, the RBCs in these disorders are much larger than normal (i.e., macrocytic). In addition, there usually are other signs of disordered hematopoiesis, such as hypersegmentation of the neutrophil nuclei. In contrast to TEC, marrow erythroblasts reveal megaloblastic changes. The specific causes of megaloblastosis are determined by measurements of RBC folate concentration, serum vitamin B12 levels, and RBC orotidine carboxylase activity. These disorders seldom are confused with TEC.
Presence of potent inhibitors of bacterial biofilm associated proteins is the key to Citrus limon’s antibiofilm activity against pathogenic Escherichia coli
Published in Biofouling, 2023
Songeeta Singha, Rajendran Thomas, Abinash Kumar, Devarshi Bharadwaj, Jai N. Vishwakarma, Vivek Kumar Gupta
The Ramachandran plot revealed the dispersion of amino acid residues of the selected protein. The 3D structure of Figure 4i of the selected protein models indicated that 91.2–96.9% of the residues were in the favorable region with 3.1–8.1% of residues in the allowed region (Figure 4ii–iii). No amino acid residues were found in disallowed regions. This study revealed that all compounds from C. limon extract interacted with the active site of target protein receptor in pathogenic E. coli (Figure 5). FabH showed higher binding energy with 5,8-dimethoxycumarin,3-methoxy-5-methylphenol,2,3-dihydrobenzofuran, orotic acid and cyclobarbital compared to the reference antibiotic kanamycin (Table 2 and Figure 6). Orotic acid bonded most effectively with FabH through five conventional hydrogen bonds at positions Asn(193) with a bond length of 2.3 Å, Asn(193) with a bond length of 2 Å, His(85) with a bond length of 2.3 Å, Thr(80) with a bond length of 2.5 Å and Thr(80) with a bond length of 2.1 Å (supplementary Table 3).
Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data
Published in Drug Metabolism Reviews, 2021
Jaydeep Yadav, Mehdi El Hassani, Jasleen Sodhi, Volker M. Lauschke, Jessica H. Hartman, Laura E. Russell
Li et al. recently studied the PK of clozapine and norclozapine in nonalcoholic fatty liver disease (NAFLD) rat model (Li et al. 2021). To evaluate the possible PK changes of clozapine and its metabolite in the early stages of NAFLD, a rat model of the disease was induced by a diet containing 1% orotic acid. In vivo experiments with rats reveal that the mechanisms by which orotic acid-supplemented diet induces liver steatosis include the activation of the sterol regulatory element-binding protein-1c (SREBP1c) (Matilainen et al. 2020). SREBP-1c, a member of the family of SREBP membrane-bound transcription factors, has been established as the principal regulator of hepatic fatty acid biosynthesis. Thus, an increase in SREBP-1c expression increases the rate of lipogenesis in the liver (Wang et al. 2011). The study showed a reduction of CYP1A1/2 activity leading to a significantly slower in vitro hepatic microsomal CLint of clozapine. As a result, the AUC of norclozapine and the AUCnorclozapine/AUCclozapine significantly increased. However, systemic exposures to clozapine after intravenous and oral administration were comparable with the control group. Furthermore, steady-state brain concentrations of the parent drug and metabolite were significantly higher in NAFLD rats compared to the control group.
The alteration of drug metabolism enzymes and pharmacokinetic parameters in nonalcoholic fatty liver disease: current animal models and clinical practice
Published in Drug Metabolism Reviews, 2023
Yan Zhu, Li Chen, Yuqi He, Lin Qin, Daopeng Tan, Zhaojun Bai, Yu Song, Yu-He Wang
Clozapine, the substrate of CYP1A2, is an atypical antipsychotic. It is mainly used for the treatment of bipolar disorder and schizophrenia (Nucifora et al. 2017; Delgado et al. 2020). The main metabolite of clozapine is norclozapine. Norclozapine is a pharmacologically active compound and has more metabolic side effects than clozapine. In orotic acid diet (OAD) rats, consistent with previous reports, the hepatic protein expression of CYP1A2 was down-regulated, resulting in a significant increase in the area under curve (AUC) and AUCnorclozapine/AUCclozapine ratios of norclozapine. In addition, higher steady-state brain concentrations of clozapine and norclozapine were observed in OAD rats. These results suggested that caution may be warranted in the use of clozapine in patients with preexisting or drug-induced NAFLD (Li et al. 2021).
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