A Dual Wavelength Differential First Derivative Spectrophotometric Method for Identification and Determination of Carbon Monoxide Generated During the Microsomal Metabolism of Xenobiotics in vitro

A dual wavelength differential first derivative spectrophotometric method has been developed to standardize the concentration of a saturated aqueous solution of carbon monoxide (CO) as the standard and to identify and to determine CO formed during the microsomal metabolism of xenobiotics in vitro. The method can significantly eliminate the background interference in the assay media and increase the quantitative accuracy and the sensitivity. There is a good linear relationship between CO concentration in the range of 2～10 μmol·L 1 CO and the distance D between the first derivative peak at 415 nm amd valley at 426 nm with r=0.9999(n=5),the regression equation being C (mmol·L 1 )=17.6D 0.4, the detection limit lower than 0.1 μmol·L 1 CO. The average recoveries of CO from the assay system and the sample were 102.1%, RSD=2.9% (n=7) and 79.7%, RSD=6.8% (n=12),respectively. The RSD of within day was 4.4%(n=18),and the RSD of day to day was 6.1%(n=16). By this method, four trihaloanilines and one trihalobenzene were tested, the results showed that only 2,4,5 trifluoroaniline could be converted to CO by the incubation with rat hepatic microsomes, NADPH and oxygen, the ability of phenobarbital or dexamethasone to induce rat hepatic microsomes to catalyze CO formation was 3 or 8 times higher than that of the control.

Complete genome sequence of the rifamycin SV-producing Amycolatopsis mediterranei U32 revealed its genetic characteristics in phylogeny and metabolism

Amycolatopsis mediterranei is used for industry-scale production of rifamycin, which plays a vital role in antimyco- bacterial therapy. As the first sequenced genome of the genus Amycolatopsis, the chromosome of strain U32 comprising 10 236 715 base pairs, is one of the largest prokaryotic genomes ever sequenced so far. Unlike the linear topology found in streptomycetes, this chromosome is circular, particularly similar to that of Saccharopolyspora erythraea and Nocardia farcinica, representing their close relationship in phylogeny and taxonomy. Although the predicted 9 228 protein-coding genes in the A. mediterranei genome shared the greatest number of orthologs with those of S. erythraea, it was unexpectedly followed by Streptomyces coelicolor rather than N. farcinica, indicating the distinct metabolic characteristics evolved via adaptation to diverse ecological niches. Besides a core region analogous to that common in streptomycetes, a novel ＇quasicore＇ with typical core characteristics is defined within the non-core region, where 21 out of the total 26 gene clusters for secondary metabolite production are located. The rifamycin biosynthesis gene cluster located in the core encodes a cytochrome P450 enzyme essential for the conversion of rifamycin SV to B, revealed by comparing to the highly homologous cluster of the rifamycin B-producing strain S699 and further confirmed by genetic complementation. The genomic information of A. mediterranei demonstrates a metabolic network orchestrated not only for extensive utilization of various carbon sources and inorganic nitrogen compounds but also for effective funneling of metabolic intermediates into the secondary antibiotic synthesis process under the control of a seemingly complex regulatory mechanism.

Identification of the metabolite and cytochrome P450 isoforms involved in rat liver microsomal metabolism of TM208

To identify the metabolite and CYP450 isoforms involved in rat liver microsomal metabolism of TM208. The present study investigated the metabolism of TM208 and the effects of selective CYP450 inhibitors on the metabolism of TM208 in rat liver microsomes. Various specific inhibitors of CYP were used to identify the isoforms of CYP involved in the metabolism of TM208. The inhibitor of CYP2D and that of CYP2B had strong inhibitory effects on TM208 metabolism in a concentration-de- pendant manner, the inhibitor of CYP1A had a modest inhibitory effect, and the inhibitor of CYP3A seemed not to have an obvious inhibitory effect on TM208 metabolism. TM208 might mainly be metabolized by CYP2D and CYP2B in rat liver microsomes.

The roles of carboxylesterase and CYP isozymes on the in vitro metabolism of T-2 toxin

Background: T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of two principal phase Ⅰ drug-metabolizing enzymes(cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.Methods: A chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry(HPLC- Qq Q MS) after a simple pretreatment.Results: In the presence of a carboxylesterase inhibitor, only 20% T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3% of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.Conclusions: Carboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The metabolite produced by carboxylesterase is HT-2, and the metabolite produced by CYP 3A4 is 3'-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin.

AMPK-associated signaling to bridge the gap between fuel metabolism and hepatocyte viability

The adenosine monophosphate-activated protein kinase (AMPK) and p70 ribosomal S6 kinase-1 pathway may serve as a key signaling flow that regulates energy metabolism; thus, this pathway becomes an attractive target for the treatment of liver diseases that result from metabolic derangements. In addition, AMPK emerges as a kinase that controls the redox-state and mitochondrial function, whose activity may be modulated by antioxidants. A close link exists between fuel metabolism and mitochondrial biogenesis. The relationship between fuel metabolism and cell survival strongly implies the existence of a shared signaling network, by which hepatocytes respond to challenges of external stimuli. The AMPK pathway may belong to this network. A series of drugs and therapeutic candidates enable hepatocytes to protect mitochondria from radical stress and increase cell viability, which may be associated with the activation of AMPK, liver kinase B1, and other molecules or components. Consequently, the components downstream of AMPK may contribute to stabilizing mitochondrial membrane potential for hepatocyte survival. In this review, we discuss the role of the AMPK pathway in hepatic energy metabolism and hepatocyte viability. This information may help identify ways to prevent and/or treat hepatic diseases caused by the metabolic syndrome. Moreover, clinical drugs and experimental therapeutic candidates that directly or indirectly modulate the AMPK pathway in distinct manners are discussed here with particular emphasis on their effects on fuel metabolism and mitochondrial function.

Resistance Level and Metabolism of Barnyard-Grass (Echinochloa crusgalli(L.) Beauv.) Populations to Quizalofop-p-ethyl in Heilongjiang Province,China

Eleven barnyardgrass populations were assayed. The highest resistant population was Geqiushan R with RI 125.45 resulted from the seed assay and 87.29 resulted from the whole plant bioassay followed by 853 R with RI 2.79 resulted from the seed assay and 6.04 resulted from the whole plant bioassay. The resistance level of other nine populations was low with RI 1.13-2.61 resulted from the seed assay and 1.48-3.63 resulted from the whole plant bioassay. The activity of an important metabolic enzyme glutathione S-transferases （GSTs） and three protective enzymes （SOD, POD, and CAT） were determined in vivo for Geqiushan R, 853 R, and Wudalianchi R. Compared with the S controls, the activities of POD in Geqiushan R, GSTs in 853 R, and Wudalianchi R were increased.

PDRG1 at the interface between intermediary metabolism and oncogenesis

PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase Ⅱ complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.

绝经后骨质疏松患者血清DPP-4、UA、P、25(OH)D_(3)水平变化及其与骨代谢指标的相关性

目的检测绝经后骨质疏松患者血清二肽基肽酶-4(DPP-4)、尿酸(UA)、孕酮(P)、25羟维生素D_(3)[25(OH)D_(3)]水平,并分析其与骨代谢指标的相关性。方法选择2022年2月至2023年2月西安医学院第一附属医院收治的320例绝经后骨质疏松患者作为观察组,并选择同期在我院接受体检的300名健康绝经女性作为对照组,比较两组受检者的血清DPP-4、UA、P、25(OH)D_(3)水平及骨代谢指标[骨钙素(OC)、I型前胶原氨基末端前肽(PINP)、β-胶联降解产物(β-CTX)及骨碱性磷酸酶(BALP)],并采用Pearson法分析血清DPP-4、UA、P、25(OH)D_(3)水平与骨代谢指标的相关性。结果观察组患者的血清DPP-4水平为(183.41±21.49)IU/L,明显高于对照组的(125.82±13.04)IU/L,UA、P、25(OH)D_(3)水平分别为(252.83±21.69)μmol/L、(1.23±0.18)nmol/L、(21.21±3.72)ng/mL,明显低于对照组的(304.34±25.77)μmol/L、(1.70±0.22)nmol/L、(32.74±3.51)ng/mL,差异均有统计学意义(P<0.05);观察组患者OC、PINP、β-CTX、BALP分别为(8.02±1.18)μg/L、(225.34±34.02)ng/mL、(0.75±0.09)ng/mL、(21.76±3.05)μg/L,明显高于对照组的(5.57±0.84)μg/L、(175.06±26.71)ng/mL、(0.45±0.06)ng/mL、(15.80±2.43)μg/L,差异均有统计学意义(P<0.05);经Pearson相关性分析结果显示,血清DPP-4与OC、PINP、β-CTX、BALP均呈正相关(P<0.05),UA、P、25(OH)D_(3)与OC、PINP、β-CTX、BALP均呈负相关(P<0.05)。结论绝经后骨质疏松患者血清DPP-4水平升高,UA、P、25(OH)D_(3)水平降低,且均与骨代谢指标具有明显相关性,临床上应予以密切关注。

Effect of Intestinal Cytochrome P450 3A on Phytochemical Presystemic Metabolism

Phytochemicals, orally administered substances, are found to undergo presystemic metabolism mainly in the intestine. Although early researches confirmed the role of intestinal bacteria in phytochemical presystemic metabolism, along with the development of molecular biology in investigating intestinal metabolism, a breakthrough has been won in research into metabolizing enzymes and transporters in intestine, which demands more attention and further studies. Recently, Cytochrome P450 3A has been found to be the most effective enzyme in mediating both oxidative （Phase Ⅰ ） and conjugative （Phase Ⅱ ） metabolism in the intestine. The present review summarizes the current findings correlated with the effect of intestinal cytochrome P450 3A on phytochemical presystemic metabolism, which provides a good basis for further research on phytochemical pharmacokinetics.

microR-1294-5p inhibits glycolytic metabolism of non-small cell lung cancer cells via targeting TMPRSS11B

Non-smallcell lung cancer(NSCLC)cells intake and consume glucose at high efficiency by aerobic glycolysis to maintain robust cell growth and resist cell death.MicroRNAs(miRNAs)have been known to play pivotal roles in NSCLC development partly through mediating glycolysis.However,only a few miRNAs have been experimentally confirmed as critical regulators of glycolysis in NSCLC.TCGA datasets were analyzed to screen for differentially expressed miRNAs between NSCLC and normal tissues.The function of miR-1294-5p was determined in NSCLC cells by cell proliferation,glucose uptake,lactate release,and Extracellular Acidification Rate(ECAR)assays.The target of miR-1294-5p was predicted by TargetScan and miRDB,which was further validated by flow cytometry analysis,RT-qPCR,western blotting,a dual-luciferase reporter assay,and RNA immunoprecipitation(RIP)assay.In the present study,it was found that miR-1294-5p was a significantly downregulated miRNA in lung adenocarcinoma(LUAD)and lung squamous cell carcinoma(LUSC).The overexpression of miR-1294-5p inhibited glycolysis,lactate export,ECAR,and cell proliferation in NSCLC cells.Analysis with bioinformatic tools,Western Blotting,RT-qPCR,flow cytometry analysis,dual-luciferase reporter assay,and RIP assay showed that miR-1294-5p directly bound to complementary sites in the 3’-Untranslated Region(UTR)of TMPRSS11B resulted in downregulation of TMPRSS11B expression.In addition,transfection of recombinant TMPRSS11B rescued the functions of miR-1294-5p on glycolysis and proliferation of NSCLC cells.The findings provided novel insights for understanding the regulation of glycolytic metabolism in NSCLC.

Regio- and Substrate-Specific Oxidative Metabolism of Terpinolene by Cytochrome P450 Monooxygenases in <i>Cupressus lusitanica</i>Cultured Cells

Many of monoterpenes produced in plants contribute to defenses against herbivores, insects and microorganisms. Among those compounds, β-thujaplicin formed in Cupressaceae plants has a unique conjugated seven-membered ring and some useful biological activities, e.g. fungicide, repellent, insecticide and so on. The biosynthesis pathway of β-thujaplicin has not yet been revealed;we have been trying to uncover it using Cupressus lusitanica cultured cells as a model. In our previous study, terpinolene was identified as a potential β-thujaplicin intermediate at the branching point to terpenoids. In this article, terpinolene metabolism in C. lusitanica cultured cells was investigated, and it was shown that the microsomal fraction from cells oxidized terpinolene into the hydroxylated compound, 5-isopropylidene-2-met-hylcyclohex-2-enol (IME). Then, IME was further oxidized by microsomal fraction to the epoxidized compound, 1,6-epoxy-4(8)-p-menthen-2-ol (EMO). These were the only two products detected from the microsomal reactions, respecttively. Moreover, microsomal reactions with monoterpenes other than terpinolene produced nothing detectable. These results show that the enzymes of these reactions had strict substrate specificity and regio-selectivity. Experiments on kinetics and with specific inhibitors confirmed that these reactions were caused by cytochrome P450 monooxygenases, respectively. These results support our hypothesis that terpinolene is a putative intermediate of β-thujaplicin biosynthesis and show that IME and EMO are also putative intermediates.

Animal plant warfare and secondary metabolite evolution

The enduring discussion,why plants produce secondary metabolites with pharmacologically and toxicologically active towards mammals traces back to the eminent role of medicinal plants in the millennia-old history of manhood.In recent years,the concept of an animal plant warfare emerged,which focused on the co-evolution between plants and herbivores.As a reaction to herbivory,plants developed mechanical defenses such as thorns and hard shells,which paved the way for adapted animal physiques.Plants evolved further defense systems by producing chemicals that exert toxic effects on the animals that ingest them.As a result of this selective pressure,animals developed special enzymes,e.g.cytochrome P450 monooxigenases(CYP450)that metabolize xenobiotic phytochemicals.As a next step in the evolutionary competition between plants and animals,plants evolved to produce non-toxic pro-drugs,which become toxic only after ingestion by animals through metabolization by enzymes such as CYP450.Because these sequestered evolutionary developments call to mind an arms race,the term animal plant warfare has been coined.The evolutionary competition between plants and animals may help to better understand the modes of action of medicinal plants and to foster the efficient and safe use of phytotherapy nowadays.

信号素分子(p)ppGpp对胸膜肺炎放线杆菌生理适应机制的影响

猪传染性胸膜肺炎是由猪胸膜肺炎放线杆菌(Actinobacillus pleuropneumoniae,APP)引起猪的一种高度接触传染性、致死性的呼吸系统传染病。1957年,Pattison等首次在英国发现该病。1990年,中国农业科学院哈尔滨兽医研究所杨旭夫等首次在我国报道该病,此后在许多省市陆续发现该病.

Early effects of Lansoprazole orally disintegrating tablets on intragastric pH in CYP2C19 extensive metabolizers

AIM: To compare rabeprazole (RPZ; 10 mg) with Lansoprazole orally disintegrating tablets (LPZ; 30 mg OD) in terms of antisecretory activity and blood drug concentration after a single dose. METHODS: Eight H pylori-negative cytochrome P450 (CYP) 2C19 extensive metabolizers were assigned to receive a single oral dose of RPZ 10 mg or LPZ 30 mg OD. Twelve hour intragastric pH monitoring was perform- ed on the day of treatment. Blood samples were also collected after the administration of each drug. RESULTS: LPZ 30 mg OD induced a significantly earlier rise in blood drug concentration than RPZ 10 mg; consequently, LPZ 30 mg OD induced a significantly earlier rise in median pH in the third and fourth hours of the study. CONCLUSION: In H pylori-negative CYP2C19 extensive metabolizers, LPZ 30 mg OD induced a significantly faster inhibition of gastric acid secretion than RPZ 10 mg.

Electrochemical and in silico approaches for liver metabolic oxidation of antitumor-active triazoloacridinone C-1305

5-Dimethylaminopropylamino-8-hydroxytriazoloacridinone(C-1305)is a promising antitumor compound developed in our laboratory.A better understanding of its metabolic transformations is still needed to explain the multidirectional mechanism of pharmacological action of triazoloacridinone derivatives at all.Thus,the aim of the current work was to predict oxidative pathways of C-1305 that would reflect its phase I metabolism.The multi-tool analysis of C-1305 metabolism included electrochemical conversion and in silico sites of metabolism predictions in relation to liver microsomal model.In the framework of the first approach,an electrochemical cell was coupled on-line to an electrospray ionization mass spectrometer.The effluent of the electrochemical cell was also injected onto a liquid chromatography column for the separation of different products formed prior to mass spectrometry analysis.In silico studies were performed using MetaSite software.Standard microsomal incubation was employed as a reference procedure.We found that C-1305 underwent electrochemical oxidation primarily on the dialkylaminoalkylamino moiety.An unknown N-dealkylated and hydroxylated C-1305 products have been identified.The electrochemical system was also able to simulate oxygenation reactions.Similar pattern of C-1305 metabolism has been predicted using in silico approach.Both proposed strategies showed high agreement in relation to the generated metabolic products of C-1305.Thus,we conclude that they can be considered as simple alternatives to enzymatic assays,affording time and cost efficiency.

PROBING THE IMPACT OF GAMMA-IRRADIATION ON THE METABOLIC STATE OF NEURAL STEM AND PRECURSOR CELLS USING DUAL-WAVELENGTH INTRINSIC SIGNAL TWO-PHOTON EXCITED FLUORESCENCE

Two-photon excitedfluorescence(TPEF)spectroscopy and imaging were used to investigate the effects of gamma-irradiation on neural stem and precursor cells(NSPCs).While the observed signal from reduced nicotinamide adenine dinucleotide(NADH)was localized to the mitochondria,the signal typically associated with oxidizedflavoproteins(Fp)was distributed diffusely throughout the cell.The measured TPEF emission and excitation spectra were similar to the established spectra of NAD(P)H and Fp.Fpfluorescence intensity was markedly increased by addition of the electron transport chain(ETC)modulator menadione to the medium,along with a concomitant decrease in the NAD(P)H signal.Three-dimensional(3D)neurospheres were imaged to obtain the cellular metabolic index(CMI),calculated as the ratio of Fp to NAD(P)Hfluorescence intensity.Radiation effects were found to differ between low-dose(
50 cGy)and high-dose(50 cGy)exposures.Low-dose irradiation caused a marked drop in CMI values accompanied by increased cellular proliferation.At higher doses,both NAD(P)H and Fp signals increased,leading to an overall elevation in CMI values.Thesefindings underscore the complex relationship between radiation dose,metabolic state,and proliferation status in NSPCs and highlight the ability of TPEF spectroscopy and imaging to characterize metabolism in 3D spheroids.

Studies on the Metabolic Pathway and Structure—Activity Relationship about the Conversion of Trifluoroanilines to Carbon monoxide by Rat Hepatic Microsomes in vitro

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The Anti-Tumor Effect of a High Caloric Diet in the PyMT Mouse Breast Cancer Model Is Initiated by an Increase in Metabolic Rate

Obesity is associated with an increased risk of mortality from certain types of cancer, including cancer of the breast. Because obesity is associated with multiple risk factors, however, the exact reasons remain unclear. The objective of this study was to determine which of the risk factors associated with obesity are related to enhanced tumor development. The MMTV-PyMT mouse model develops mammary tumors which share numerous characteristics with those of humans. We challenged these mice with a high fat/high carbohydrate, high caloric (HC) diet, and looked for relationships between enhanced primary tumor development and adiposity, various aspects of glucose homeostasis, and metabolic factors. The HC diet enhanced tumor progression in PyMT mice. While mice on the HC diet also developed increased adiposity, hyperglycemia and hyperinsulinemia, none of these risk factors was found to be associated with the observed increases in tumor growth. Rather, we found that while overall, tumor growth was enhanced in HC diet-fed mice compared to those maintained on a regular diet, it was attenuated in individuals by an HC diet-induced increase in metabolic rate and decrease in respiratory exchange ratio. Tumor size in HC diet-fed mice was directly related to p38 phosphorylation and Bcl-2 inhibition, and the degree of vascularization of these tumors was closely and indirectly related to the rate of mouse oxygen consumption. The data suggest that an increase in metabolic rate and oxygen consumption, induced by the introduction of a high caloric diet, has a protective effect against tumor growth by increasing the activity levels of the tumor suppressor p38 and decreasing the activity of the antiapoptoic protein Bcl-2, as well as by reducing hypoxia-induced tumor vascularization.

Influences of V5-epitope tag on the metabolic activation of AFB1 by human cytochrome P450 2A13

Objective： To explore the impact of V5-epitope tag inserted in the commercial pcDNA5/FRT/V5-His TOPO expression vector on the metabolic activation of AFB1 by human CYP2A13. Methods ： A C-terminal 6 × Histag was first introduced into CYP2A13 cDNA by PCR and subsequently transferred into the expressing vector pcDNA5/FRT. Another commercial pcDNA5/FRT/V5-His TOPO expression vector was used to develop the construct directly via PCR. Both of the constructs were then transfected into Flp-In CHO and allowed for the stable expression of CYP2A13. The mouse CYP2A5 and the vector alone were used as positive and negative control, respectively. The presence of CYP2A5 and CYP2A13 cDNA and their protein expression in the stable transfectant cells were deterrrfined by immunoblotting assay using a monoclonal antibody against 6 × Histag. The AFBl-induced cytotoxicity in these tranfected CHO cells were conducted by MTS assay and the IC50 of cell viability was used to compare the CYP enzyme metabolic activity in AFB1 metabolism among these cells. Results： In accordance with the Flp-In system working mechanism, all the transfectant cells presented same protein expression level. The CHO cells expressing CYP2A5 was more sensitive to AFB1 treatment than those cells expressing CYP2A13, there was about 30-fold ICs0 difference between the two cells （2.1 nmol/L vs 58 nmol/L）. Interestingly, CYP2A13 fused with V5-Histag had the lost of metabolic activity to AFB1 than that fused with Histag alone, the ICa, of the viability in CHO-2A13-His-V5 cells was about 20-fold less than CHO-2A13- His （〉 1 000 nmol/L vs 58 nmol/L）. However, there was no change between CYP2A5 fused with V5-Histag and Histag alone （2.4 nmol/L vs 2.1 nmol/L）. Conclusion： The results demonstrate that CYP2A13 fused with V5-epitope has a significant impact on its metabolic activation to AFB1, which indicated that it should be careful to select a new expressing vector for evaluating the enzyme activity in carcinogen metabolism.

中枢神经系统药物转运体P-糖蛋白的表达水平变化对儿童药物代谢的影响

药物转运体P-糖蛋白属于结合盒式蛋白转运体蛋白家族,其可将小分子物质等排出大脑,有效地减少或阻止药物进入脑组织,从而发挥中枢神经系统保护作用。但对脑组织的药物转运体P-糖蛋白在新生儿出生后表达水平变化的研究较少。本文综述了药物转运体P-糖蛋白在中枢神经系统的外排转运功能、儿童中枢神经系统表达量变化、中枢神经系统发育早期阶段P-糖蛋白表达量对脑组织药物浓度的影响、动物外推至人类药代动力学模型以及内含P-糖蛋白的中枢神经系统生理药代动力学模型研究,为药物转运体P-糖蛋白底物在儿童生理药代动力学研究提供参考。