Spatiotemporal pharmacometabolomics based on ambient mass spectrometry imaging to evaluate the metabolism and hepatotoxicity of amiodarone in HepG2 spheroids / 药物分析学报

Three-dimensional(3D)cell spheroid models combined with mass spectrometry imaging(MSI)enables innovative investigation of in vivo-like biological processes under different physiological and patho-logical conditions.Herein,airflow-assisted desorption electrospray ionization-MSI(AFADESI-MSI)was coupled with 3D HepG2 spheroids to assess the metabolism and hepatotoxicity of amiodarone(AMI).High-coverage imaging of＞1100 endogenous metabolites in hepatocyte spheroids was achieved using AFADESI-MSI.Following AMI treatment at different times,15 metabolites of AMI involved in N-desethylation,hydroxylation,deiodination,and desaturation metabolic reactions were identified,and according to their spatiotemporal dynamics features,the metabolic pathways of AMI were proposed.Subsequently,the temporal and spatial changes in metabolic disturbance within spheroids caused by drug exposure were obtained via metabolomic analysis.The main dysregulated metabolic pathways included arachidonic acid and glycerophospholipid metabolism,providing considerable evidence for the mechanism of AMI hepatotoxicity.In addition,a biomarker group of eight fatty acids was selected that provided improved indication of cell viability and could characterize the hepatotoxicity of AMI.The combination of AFADESI-MSI and HepG2 spheroids can simultaneously obtain spatiotemporal infor-mation for drugs,drug metabolites,and endogenous metabolites after AMI treatment,providing an effective tool for in vitro drug hepatotoxicity evaluation.

Comparison of bacterial and human drug metabolizing enzymes in database and prospect of influence of intestinal bacteria on drug metabolism / 中国药科大学学报

@#This study focused on various databases and literatures related to drug metabolism, collated and analyzed the information related to bacterial and human drug metabolic enzymes, and compared the similarities and differences between the information included in the database of bacterial and human drug metabolic enzymes. Results found more bacterial drug metabolic enzymes than human drug metabolic enzymes (9 703 vs 964), but much less than the total number of bacterial enzymes in BRENDA database (9 703 vs 20 835 235), indicating that the influence of bacteria on drug metabolism could have been greatly underestimated, and that further systematic research is needed.We summarized the progress and shortcomings of the current research on the influence of intestinal flora on drug metabolism, and proposed a research idea, that is, to predict through artificial intelligence whether intestinal bacterial proteins have the ability to metabolize drugs, to verify their biological functions by in vitro/in vivo experiments and gene editing, and to establish a database of drug metabolic enzymes from intestinal bacteria with complete annotation functions, in an attempt to provide a solid theoretical basis for further exploration of the effects of intestinal flora on drug metabolism.

Drug selection for simultaneous treatment of tuberculosis combined with hepatitis C virus infection / 中华肝脏病杂志

Clinically, patients with tuberculosis (TB) combined with hepatitis C virus (HCV) infection often require simultaneous treatment. Consequently, when anti-HCV and TB drugs are used in combination drug-drug interactions (DDIs), anti-TB drug-induced hepatotoxicity, and liver disease states need to be considered. This paper focuses on discussing the metabolic mechanisms of commonly used anti-TB and HCV drugs and the selection options of combined drugs, so as to provide rational drug use for TB patients combined with HCV infection.

Advances in the Function of Cytochrome P450 Enzymes in Brain and Their Research Progress in Neuropsychiatric Disease / 中国药学杂志

Cytochrome P450 enzymes participate in the biotransformation of various organic compounds in living organisms. Cytochrome P450 enzymes are present and active in various brain regions, which mediate the synthesis and metabolism of various endogenous substances in the brain, so the enzymes play an important role in maintaining homeostasis of the central nervous system. And cytochrome P450 enzymes in brain are widely involved in metabolism of central drugs such as tramadol, so the changes of their activities or expressions may affect the drug's efficacy in brain. In addition, in view of the important roles of cytochrome P450 enzymes in the biotransformation of endogenous and exogenous substances in brain, the importance of their genetic polymorphism or activity changes in neuropsychiatric diseases is being gradually described. Therefore, in order to provide theoretical basis for the development of related targeted therapeutic drugs and explore whether cytochrome P450 enzymes in the brain can be used as therapeutic targets for central diseases, the development in the function of cytochrome P450 enzymes in brain and their recent advances in neuropsychiatric diseases by reviewing the relevant research in recent years are summarized.

Advances in long non-coding RNA in chemotherapeutic resistance of hepatocellular carcinoma / 解放军医学杂志

Hepatocellular carcinoma (HCC), as a global malignant tumor with high morbidity and mortality, has seriously endangered human health. In the treatment of HCC, chemotherapy resistance is the knotty problem. Long non-coding RNA (lncRNA), as a new multifunctional molecule with complex mechanisms, plays a role in the biological processes of HCC, such as development, progression, invasion and migration, and participates in the complex mechanism of drug resistance through abnormal regulation of gene expression. In this paper, to seek for the new method for solving the chemotherapeutic resistance of HCC based on the research of lncRNA, the effect and mechanism of lncRNA on chemotherapeutic resistance of HCC were summarized.

The effect of species difference in carboxylesterase on the drug metabolism / 国际药学研究杂志

Carboxylesterase(CES), the most abundant hydrolase in humans and animals, participates in the metabolism of various endogenous and exogenous compounds and drugs. The distribution and activity of CES have obvious species differences in hu mans and animals, which are closely related to the pharmacokinetics(PK), pharmacodynamics(PD)and toxic side effect of drugs. Therefore, this paper summarizes the effects of the difference in the classification, distribution, induction and inhibition of CES as well as the effects of species difference in plasma, liver, small intestine and skin on the metabolism of ester prodrugs, so as to provide a reference for the correct selection of experimental animals in preclinical studies of new drugs to accurately predict the clinical PK, PD and toxicological effects.

Advances in research on the impact of the plateau environmental on the drug metabolism / 药学实践杂志

Plateau environment will affect the metabolism of drugs in the body, which will cause changes in pharmacokinetic parameters, expression and function of drug metabolizing enzymes and transporters. With the rapid development of the pharmaceutical industry, therapeutic drug monitoring (TDM) has been widely paid attention to as a basis for personalized drugs. What impact does the plateau environment on monitoring drugs? In this literature review, we will summarize the types of commonly used therapeutic monitoring drugs, therapeutic windows, and blood samples, analyze the effects of plateau hypoxic environment on the metabolism of commonly used monitoring drugs, provide a reference for the clinical treatment and monitoring drugs of plateau, better ensure the rational use of drugs in the plateau population, and also provide a reference for the later research group to conduct the monitoring of plateau therapeutic drugs and the selection of research drugs.

Long-noncoding RNAs (lncRNAs) in drug metabolism and disposition, implications in cancer chemo-resistance

Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters. Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability (pharmacokinetics, or PK) and therapeutic efficacy (pharmacodynamics, or PD) of drugs. Recent studies have suggested that the long non-coding RNAs (lncRNAs) are highly relevant to drug metabolism and drug resistance, including chemo-resistance in cancers, through the regulation of drug metabolism and disposition related genes. This review summarizes the regulation of enzymes, transporters, or regulatory proteins involved in drug metabolism by lncRNAs, with a particular emphasis on drug metabolism and chemo-resistance in cancer patients. The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related lncRNAs are also proposed. Understanding the role of lncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms, but also enable the discovery of lncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients, including cancer patients.

Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model

We examined the impact of gut inflammation on the expression of cytochrome P450 (P450) and other biotransformation genes in male mice using a dextran sulfate sodium (DSS)-induced colitis model. Several P450 isoforms, including CYP1A, CYP2B, CYP2C, and CYP3A, were down-regulated, accompanied by decreases in microsomal metabolism of diclofenac and nifedipine, in the liver and small intestine. The impact of the colitis on clearance of oral drugs varied for four different drugs tested: a small decrease for nifedipine, a relatively large decrease for lovastatin, but no change for pravastatin, and a large decrease in the absorption of cyclosporine A. To further assess the scope of influence of gut inflammation on gene expression, we performed genome-wide expression analysis using RNA-seq, which showed down-regulation of many CYPs, non-CYP phase-I enzymes, phase-II enzymes and transporters, and up-regulation of many other members of these gene families, in both liver and intestine of adult C57BL/6 mice, by DSS-induced colitis. Overall, our results indicate that gut inflammation suppresses the expression of many P450s and other biotransformation genes in the intestine and liver, and alters the pharmacokinetics for some but not all drugs, potentially affecting therapeutic efficacy or causing adverse effects in a drug-specific fashion.

Effects of total parenteral nutrition on drug metabolism gene expression in mice

Parenteral nutrition-associated liver disease (PNALD) is a liver dysfunction caused by various risk factors presented in patients receiving total parenteral nutrition (TPN). Omega-6 rich Intralipid® and omega-3 rich Omegaven® are two intravenous lipid emulsions used in TPN. TPN could affect the hepatic expression of genes in anti-oxidative stress, but it's unknown whether TPN affects genes in drug metabolism. In this study, either Intralipid®- or Omegaven®-based TPN was administered to mice and the expression of a cohort of genes involved in anti-oxidative stress or drug metabolism was analyzed, glutathione (GSH) levels were measured, and protein levels for two key drug metabolism genes were determined. Overall, the expression of most genes was downregulated by Intralipid®-based TPN ( and ). Omegaven® showed similar results as Intralipid® except for preserving the expression of and and increasing . Total GSH levels were decreased by Intralipid®, but increased by Omegaven®. CYP3A11 protein levels were increased by Omegaven®. In conclusion, TPN reduced the expression of many genes involved in anti-oxidative stress and drug metabolism in mice. However, Omegaven® preserved expression of , suggesting another beneficial effect of Omegaven® in protecting liver functions.

Screening of the whole human cytochrome P450 complement (CYPome) with enzyme bag cocktails / 药物分析学报

We have previously introduced the use of permeabilized fission yeast cells (enzyme bags) that recom-binantly express full-length CYPs for drug metabolism studies. Such enzyme bags are cells with pores that function as enzymes in situ. They can easily be prepared without a need for ultracentrifugation and may be used in similar protocols as microsomes. In this study we report the preparation of enzyme bag cocktails that permit the testing of multiple CYPs in a single enzyme bag reaction. Moreover, we established a convenient testing scheme that permits a rapid screen of all human CYPs for activity to-wards any given candidate substrate. An important aspect of this approach is the reduction of individual CYP test assays. If a cocktail containing many CYPs tests negative, it follows that all CYPs included in that cocktail need not be tested individually, thus saving time and resources. The new protocol was validated using two probe substrates.

In vitro and in vivo effect of Eurycoma longifolia root extract on UDP-glucuronosyltransferase activity

The aim of this research was to evaluate the effects of Eurycoma longifolia root extract (ELE) on enzymes activity in thephase II drug metabolism on Sprague-Dawley (SD) rats, especially on uridine 5ʹ-diphospho-glucuronosyltransferase(UGT) activity, in vivo and in vitro. The UGT assay was performed as follows: for the in vivo study, the male SDrats were treated with ELE at doses ranging from 5 to 1,000 mg/kg b.w. and 5, 25, and 50 mg/kg b.w for acuteand sub-acute study, respectively. The ELE concentrations of 0.01 to 1,000 µg/ml were used for in vitro study. Thep-nitrophenol (pNP) that consumed in the glucuronidation process reflected the UGT activity and was calculated usingstandard curve of pNP. UGT enzyme activity was inhibited significantly (p < 0.01) by ELE extract in the male rat forboth acute and sub-acute experiments. ELE extract decreased the enzyme activity significantly (p < 0.01), at all theconcentrations tested in the in vitro experiment when compared to the negative control group. ELE had a lower activity(the IC50 of 0.74 µg/ml) as compared to Na diclofenac (positive control) with an IC50 of 0.17 µg/ml. Eurycomalongifolia decreased the UGT enzyme activity significantly (p < 0.01), both for in vivo and in vitro study

Herramientas farmacométricas para antichagásicos, aplicadas a estudios fármaco y toxicocinéticos en contexto pediátrico / Pharmacometric tools for antihagasics, applied to drug and toxicokinetic studies in a pediatric context

La enfermedad de Chagas afecta aproximadamente a 10 millones de personas en Sudamérica y 1,5 millones en la Argentina. La transmisión congénita es la más importante en áreas urbanas. Existen dos drogas aprobadas para el tratamiento: nifurtimox (Laboratorios Bayer) y benznidazol (BNZ) (Laboratorios Roche, LAFEPE y Elea) que fueron desarrolladas hace más de 40 años y cuya farmacología y metabolismo en humanos han sido poco estudiados. La información disponible es virtualmente inexistente en niños y mujeres embarazadas. Se busca aportar estudios sistemáticos hacia una farmacoterapéutica racional en niños ya que empíricamente ha demostrado gran efectividad. Se desarrollaron métodos bioanalíticos aplicables a matrices biológicas como plasma, orina y leche materna para las drogas madres y la identificación de metabolitos en muestras de pacientes bajo terapéutica. La farmacocinética poblacional pediátrica descripta aquí para BNZ es concluyente respecto de sus diferencias con la farmacocinética en adultos. Se identificaron tres compuestos presentados como metabolitos del BNZ. La transferencia de dicho fármaco a la leche materna no supone riesgo para el lactante. Estos resultados brindan información para mejorar los protocolos de tratamiento existentes buscando una farmacoterapéutica adaptada a la edad y un uso más seguro de los fármacos en niños y eventualmente en adultos.

Chagas disease affects approximately 10 million people in South America and 1.5 million in Argentina. Congenital transmission is most important in urban areas. There are two drugs approved for treatment: nifurtimox (Bayer) and benznidazole (BNZ) (Roche, LAFEPE, Elea),developed more than 40 years ago. Their pharmacology and metabolism in humans have been seldom studied. The information available on children and pregnant women is virtually non-existent. The aim of this study is to provide systematic studies towards a rational pharmacotherapeutic sin children, which has been empirically proven to be highly effective. Bioanalytical methods were developed for plasma, urine and breast milk for parent drugs and for the identification of their metabolites in samples of patients under treatment. The pediatric population pharmacokinetics described here for BNZ is conclusive about their differences from adult pharmacokinetics. Three compounds presented as BNZ metabolites were identified. The transfer of this drug to the breast milk does not present a risk to the infant. These evidences offer information to improve the existing treatment protocols, seeking a pharmacotherapy adapted to the age and a safer use of the drugs in children and eventually in adults.

A doença de Chagas afeta aproximadamente 10 milhões de pessoas na América do Sul e 1,5 milhão na Argentina. A transmissão congênita é a mais importante em áreas urbanas. Existem dois medicamentos aprovados para o tratamento: nifurtimox (Laboratórios Bayer) e benznidazol (BNZ) (Laboratórios Roche, LAFEPE e Elea), desenvolvidas há mais de 40 anos, e sua farmacologia e seu metabolismo em humanos têm sido pouco estudados. A informação disponível é praticamente inexistente em crianças e mulheres grávidas. O objetivo é fornecer estudos sistemáticos para uma farmacoterapêutica racional em crianças visto que foram comprovadas empiricamente como sendo altamente eficazes. Métodos bioanalíticos aplicáveis a matrizes biológicas como plasma, urina e leite materno para fármacos-mãe e para a identificação de metabólitos em amostras de pacientes em tratamento terapêutico foram desenvolvidos. A farmacocinética da população pediátrica aqui descrita para BNZ é conclusiva em relação às suas diferenças com a farmacocinética de adultos. Três compostos apresentados como metabólitos do BNZ foram identificados. A transferência do referido medicamento para o leite materno não representa risco para o lactente. Essas evidências oferecem informações para melhorar os protocolos de tratamento existentes, buscando uma farmacoterapia adaptada à idade e um uso mais seguro dos medicamentos em crianças e eventualmente em adultos.

Role of vitamin D receptor in the regulation of gene expression

Vitamin D (VD) is a multifunctional nutrient which can be either synthesized or absorbed from the diet. It plays a pivotal role in systemic calcium and phosphate homeostasis, as well as in various physiological and pathological processes. VD is converted to the active form, 1,25-dihydroxyvitamin D (1,25-D3), by cytochrome P450 2R1 (CYP2R1)/CYP27A1 and CYP27B1 sequentially, and deactivated by multiple enzymes including CYP3A4. On the other hand, 1,25-D3 is capable of activating the transcription of genes in humans, mice and rats. The vitamin D receptor (VDR)-mediated transactivation of human and resembles that known for pregnane X receptor (PXR). Activated VDR forms a heterodimer with retinoid X receptor (RXR), recruits co-activators, translocates to the cell nucleus, binds to the specific vitamin D responsive elements (VDRE), and activates the gene transcription. In mice, intestinal mRNA levels, but not those of hepatic CYP3As, were induced by administration of VDR and PXR agonists. In rats, intestinal and mRNAs were induced by 1,25-D3 or lithocholic acid (LCA), whereas hepatic , but not and , was modulated to 1,25-D3 treatment. In general, the VDR-mediated regulation of CYP3A presents species and organ specificity.

Current trends in drug metabolism and pharmacokinetics

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

Effects of intestinal microflora on drug metabolism / 中国药理学通报

A large number of gut flora communities have colonized in the intestine, which is crucial to the metabolism of foreign compounds such as drugs. In recent years, the gut flora has been widely regarded as the "invisible organ" of the body. By reviewing the pertinent literature at home and abroad, classifications and functions of intestinal flora and its influence on the chemical composition and chemical metabolism of Chinese medicine are analyzed in the article. Understanding the impact of intestinal flora on drug metabolism and the process of drug conversion has great significance in guiding clinical rational drug use and individual therapy, evaluating toxicity and promoting drug discovery and development, and providing theoretical guidance for the study of the effects of intestinal flora on drug metabolism in the plateau environment.

Next generation sequencing analysis of drug metabolism related IncRNA in children after living donor liver transplantation / 中华器官移植杂志

Objective To employ high-throughput next generation sequencing (NGS) for analyzing the expression of lneRNAs and mRNAs in donor samples from pediatric living donor liver transplantation and search differentially expressed lncRNAs and drag metabolic gene for individualized guidance of immunosuppressive agents.Methods Between October 2016 and December 2017,10 liver tissue specimens from living donor liver transplantation children were collected and divided into fast and slow metabolic groups (n =5 each) according to the postoperative profiles of drug metabolism.Samples were assayed for high-throughput NGS.Target analysis was used for functional pathways and screening target genes prediction.Results There were differentially expressed 908 mRNAs and 1228 lncRNAs between slow metabolic and fast metabolic groups (P＜0.05).According to the abundance and difference,22 up-regulated and 18 down-regulated mRNAs,13 up-regulated and 24 down-regulated lncRNAs were selected.In addition to CYP3A5,CYP2C19,CYP1A2 and UGT1A1 might affect the metabolism of tacrolimus.At the same time,NONHSAT108617.2 in differemially expressed lncRNAs might regulate the expression of CYP3A5 gene.Conclusions This study has comprehensively analyzed the expression of lncRNAs in donor liver from pediatric liver transplantation.Some differentially expressed drug metabolism related genes may affect tacrolimus metabolism in vivo and thus the postoperative use of immunosuppressive drugs.

Drug Metabolism and Disposition in Australian Marsupial Koala (Phascolarctos cinereus)

Aims: Koalas are unique obligated eucalyptus feeding Australian marsupials that often require medical treatments after wildlife rehabilitation across Australia. At present, little is known about the pharmacology and pharmacokinetics of drugs commonly used in koalas and how koalas handle and detoxify toxic chemicals from both environmental exposure and their unique eucalyptus diet. The aim of this study is to summarise and critically evaluate the current literature on what is known about the pharmacokinetics (absorption, distribution, metabolism, and excretion ADME) of drugs frequently used in koalas, including antibiotics fluoroquinolones, fluconazole, chloramphenicol and analgesics. Methodology: Literature regarding drug disposition and pharmacokinetic studies of therapeutic agents commonly used in koalas over the last decade has been critically reviewed. Some older sources from the primary literature search have also been included to determine the background information leading to current rationale behind drug indication, dosage, and route of administration in marsupial koalas and related species. Results: Most studies reported a much lower bioavailability of orally administered drugs in koalas compared to that in humans and other species. Current dosing regimens do not prove to be effective or optimal in order to achieve the best treatment outcomes. It seems likely that oral administration of many drugs in koalas exhibited poor bioavailability due to poor absorption and might be extensive metabolism via hepatic and intestinal enzymes. Conclusion: Collectively, the findings suggest the need for further pharmacokinetic studies to investigate alternative routes of administration for many commonly used drugs in marsupial koalas, including antibiotics, anaesthetics, and analgesic medicines.

Neonatal activation of Pxr results in persistent altered expression of DMEs in adult mice / 中国药理学与毒理学杂志

OBJECTIVE To demonstrate the long-or short-term impacts of neonatal Pxr(pregnane X receptor) agonists exposureon DMEs (drug metabolism enzymes) expression in adulthood. METHODS C57BL/6 mice(day 5,postnatal)were injected with different doses(0,50,100,150,200 mg·kg-1·d-1, constitutive 4 d)of PCN(pregnenolone-16a-carbonitrile).Mice at different ages(day 5,10,15,25,postna-tal)were administrated with 200 mg·kg-1·d-1PCN in constitutive 4 d.All mice were sacrificed at day 60 after birth. Liver samples were collected for detecting the expression of Pxr target genes. RESULTS Compared with vehicle group, the significant inductions of Cyp2b10, Cyp3a11 and Pxrwere observed in high dose groups (150, 200 mg·kg-1·d-1, 5-8 d after birth) both in male and female mice (n=4-9/group,P<0.05).Furthermore,high dose groups(200 mg·kg-1·d-1,5-8 d after birth)were found to have higher mRNA expression levels of Cyp2a4,Ugt1a1,Abcc4,and Oatpla4 in female mice,while Papss2 in male mice compared with vehicle groups (n= 4-9/group, P<0.05). Interestingly, a decreased mRNA expression of Sult2a1 was identified in 200 (5-8 d) groups (n=4-9/group, P<0.05). Consistent with these results, the protein expression of Cyp3a11 was only increased in 200 (5-8 d) groups compared with the vehicle groups(n=3/group,P<0.05).Importantly,the persistent impacts on DMEs only occurred in day 5 and day 25 treatment groups,not day 10 and day 15 groups(n=4/group).CONCLUSION Neonatal Pxr activation has a long-term effect on the expression of DMEs in C57BL/6 mice.Dose and treatment exposure time are two key factors involved in this permanent alteration procedure.

Impacts of maternal LPS exposure on proinflammatory cytokines and DMEs expression in mouse offspring / 中国药理学与毒理学杂志

OBJECTIVE To explore the effects of perinatal inflammation on the expression of proin-flammatory cytokines and DMEs (drug metabolism enzymes) in offspring mice. METHODS C57BL/6 maternal mice were administrated with single dose 100 μg·kg-1LPS(lipopolysaccharide)or saline(vehicle) during gestation (day 10 after fertilization). Offspring mice were sacrificed at 30 d after birth and liver samples were collected.Real-time PCR was adopted to test the mRNA expression of proinflammatory cytokines (Nrlp3 and IL-1β), nuclear receptors (Pxr and Car), and DMEs (Cyp3a11, 2b10, 1a2, and Ugt1a1).RESULTS Gender different expression of candidate genes was observed.The expression of Car,in the maternal injection of LPS groups,was significantly decreased in both female and male offspring (n=3-8/group, P<0.01). Concomitantly, a significantly lower expression of Cyp3a11 was found in both female and male offspring (P<0.01, P<0.05, respectively). Furthermore, the expression of Ugt1a1 was reduced in male offspring following maternal administration of LPS (P<0.01). In male offspring, Nrlp3 expression was specially decreased(P<0.05).Interestingly,there was an approximately 66% reduction in mRNA level of Cyp1a2 in female offspring (P<0.01), while in male offspring Cyp1a2 expression showed an increased trend (P>0.05) compared with vehicle group. The expression of Pxr, Cyp2b10, and IL-1β was no difference between LPS treatment group and vehicle group(P>0.05).CONCLUSION Maternal LPS administration affects the expression of proinflammatory cytokines, nuclear receptors and DMEs in mouse offspring.