Quantitative Proteomics Reveals Changes in Transporter Protein Abundance in Liver, Kidney and Brain of Mice by Pregnancy

Liao, Michael Z.; Gao, Chunying; Bhatt, Deepak; Prasad, Bhagwat; Mao, Qingcheng

doi:10.2174/1872312812666180625122810

Cited by 9 publications

(8 citation statements)

References 28 publications

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“…Targeted Proteomic Analysis of Hepatic DMETs by LC-MS/MS. Quantification of relative protein abundance of major DMETs in the liver tissues of CV and GF mice was done by quantitative LC-MS/MS proteomic analysis using methods previously described (Bhatt and Prasad, 2018;Liao et al, 2018;Prasad et al, 2018). For P450 enzymes, changes in protein levels of CYP2C37, CYP2C50, CYP2C54, CYP2D22, CYP2D40, CYP3A11, CYP3A16, and CYP3A41 were quantified.…”

Section: Methodsmentioning

confidence: 99%

Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy

Han¹,

Wang²,

Shi³

et al. 2020

Drug Metab Dispos

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The microbiome and pregnancy are known to alter drug disposition, yet the interplay of the two physiologic factors on the expression and/or activity of drug metabolizing enzymes and transporters (DMETs) is unknown. This study investigated the effects of microbiome on host hepatic DMETs in mice during pregnancy by comparing four groups of conventional (CV) and germ-free (GF) female mice and pregnancy status, namely, CV nonpregnant, GF non-pregnant, CV pregnant, and GF pregnant mice. Transcriptomic and targeted proteomics of hepatic DMETs were profiled by using multiomics. Plasma bile acid and steroid hormone levels were quantified by liquid chromatography tandem mass spectrometry. CYP3A activities were measured by mouse liver microsome incubations. The trend of pregnancy-induced changes in the expression or activity of hepatic DMETs in CV and GF mice was similar; however, the magnitude of change was noticeably different. For certain DMETs, pregnancy status had paradoxical effects on mRNA and protein expression in both CV and GF mice. For instance, the mRNA levels of Cyp3a11, the murine homolog of human CYP3A4, were decreased by 1.7-fold and 3.3-fold by pregnancy in CV and GF mice, respectively; however, the protein levels of CYP3A11 were increased similarly ∼twofold by pregnancy in both CV and GF mice. Microsome incubations revealed a marked induction of CYP3A activity by pregnancy that was 10-fold greater in CV mice than that in GF mice. This is the first study to show that the microbiome can alter the expression and/or activity of hepatic DMETs in pregnancy. SIGNIFICANCE STATEMENTWe demonstrated for the first time that microbiome and pregnancy can interplay to alter the expression and/or activity of hepatic drug metabolizing enzymes and transporters. Though the trend of pregnancy-induced changes in the expression or activity of hepatic drug metabolizing enzymes and transporters in conventional and germ-free mice was similar, the magnitude of change was noticeably different.

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Section: Methodsmentioning

confidence: 99%

Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy

Han¹,

Wang²,

Shi³

et al. 2020

Drug Metab Dispos

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“…Quantitative proteomics can selectively and precisely quantify BBB transporters, such as P-gp, BCRP, and MRPs. 34,94 Also, variable transporter expression plays a crucial role in the etiology and pathogenesis of different brain diseases such as Alzheimer's disease, epilepsy, Creutzfeldt-Jakob disease, and Parkinson's disease. For effective treatment of central nervous system disorders, a drug must reach a target site in the brain.…”

Section: Other Diseasesmentioning

confidence: 99%

“…In brain disorders, the effectiveness of drug therapy is often reduced because of the resistance, which is caused by increased expression of efflux transporters (eg, P‐gp) at the blood‐brain barrier (BBB). Quantitative proteomics can selectively and precisely quantify BBB transporters, such as P‐gp, BCRP, and MRPs 34,94 . Also, variable transporter expression plays a crucial role in the etiology and pathogenesis of different brain diseases such as Alzheimer's disease, epilepsy, Creutzfeldt‐Jakob disease, and Parkinson's disease.…”

Section: Impact Of Disease Conditions On Drug Disposition and The Potmentioning

confidence: 99%

Utility of Quantitative Proteomics for Enhancing the Predictive Ability of Physiologically Based Pharmacokinetic Models Across Disease States

Sharma

Ahire

2020

The Journal of Clinical Pharma

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Disease states such as liver cirrhosis and chronic kidney disease can lead to altered pharmacokinetics (PK) of drugs by influencing drug absorption, blood flow to organs, plasma protein binding, apparent volume of distribution, and drug-metabolizing enzyme and transporter (DMET) abundance. Narrow therapeutic index drugs are particularly vulnerable to undesired pharmacodynamics (PD) because of the changes in drug PK in disease states. However, systematic clinical evaluation of disease effect on drug PK and PD is not always possible because of the complexity or the cost of clinical studies. Physiologically based PK (PBPK) modeling is emerging as an alternate method to extrapolate drug PK from the healthy population to disease states. These models require information on the effect of disease condition on the activity or tissue abundance of DMET proteins. Although immunoquantification-based abundance data were available in the literature for a limited number of DMET proteins, the emergence of mass spectrometry-based quantitative proteomics as a sensitive, robust, and high-throughput tool has allowed a rapid increase in data availability on tissue DMET abundance in healthy versus disease states, especially in liver tissue. Here, we summarize these data including the available immunoquantification or mRNA levels of DMET proteins (healthy vs disease states) in extrahepatic tissue and discuss the potential applications of DMET abundance data in enhancing the capability of PBPK modeling in predicting drug disposition across disease states. Successful examples of PBPK modeling that integrate differences in DMET proteins between healthy and disease states are discussed.

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“…Pregnancy improves the early entry of the cell cycle of hepatocytes, hepatic fat accumulation, and hepatocyte mitosis, which have positive effects on maternal liver regeneration following partial hepatectomy in mice (Lee et al, 2020). There are significant changes in protein abundance of major drug/xenobiotic transporters in the maternal liver of mice during pregnancy (Liao et al, 2018). It has been reported that early pregnancy enhances expression of progesterone (P4) receptor, P4‐induced blocking factor (Zhang et al, 2019), cyclooxygenase‐2, prostaglandin (PG) E synthase, PGF synthase (Yang, Han, et al, 2020), interferon‐stimulated genes (Yang, Li, et al, 2020), and interleukin (IL)‐5 (Yang et al, 2019) in the maternal liver during early pregnancy in sheep.…”

Section: Introductionmentioning

confidence: 99%

“…There are significant changes in protein abundance of major drug/ xenobiotic transporters in the maternal liver of mice during pregnancy (Liao et al, 2018). It has been reported that early pregnancy enhances expression of progesterone (P4) receptor, P4-induced blocking factor (Zhang et al, 2019), cyclooxygenase-2, prostaglandin (PG) E synthase, PGF synthase (Yang, Han, et al, 2020), interferon-stimulated genes , and interleukin (IL)-5 (Yang et al, 2019) in the maternal liver during early pregnancy in sheep.…”

mentioning

confidence: 99%

Early pregnancy regulates expression of complement components in ovine liver

Feng

Yang

Zhang

et al. 2021

Animal Science Journal

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Complement pathways participate in the regulation of innate immune system, and complement activation is inhibited in normal pregnancy. The liver plays key roles in the modulation of immunity and tolerance, but it is unclear that early pregnancy induces the changes in expression of complement components in the ovine maternal liver. The aim of the present study was to explore the expression of complement components in the liver using quantitative real‐time polymerase chain reaction (PCR), Western blot, and immunohistochemistry. Maternal livers were collected on Day 16 of the estrous cycle and Days 13, 16, and 25 of gestation. The results indicated that early pregnancy suppressed the expression of C1q, C1r, C1s, C2, C4a, C5b, and C9 in the maternal liver, but C3 expression was increased. In addition, C3 protein was located in the endothelial cells of the proper hepatic arteries and portal veins and hepatocytes. In summary, the downregulaltion of C1q, C1r, C1s, C2, C4a, C5b, and C9 may be involved in the suppression of complement activation, and upregulation of C3 is related to the modulation of maternal immune tolerance in ovine liver.

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Quantitative Proteomics Reveals Changes in Transporter Protein Abundance in Liver, Kidney and Brain of Mice by Pregnancy

Abstract: Protein abundance of drug transporters can be significantly changed particularly in the liver by pregnancy. These results will be helpful to understand pregnancy-induced changes in drug/xenobiotic disposition in the mouse model.

Cited by 9 publications

References 28 publications

Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy

Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy

Utility of Quantitative Proteomics for Enhancing the Predictive Ability of Physiologically Based Pharmacokinetic Models Across Disease States

Early pregnancy regulates expression of complement components in ovine liver

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