Changes of Transporters and Drug-metabolizing Enzymes in Nephrotic Syndrome

2020 ◽  
Vol 21 (5) ◽  
pp. 368-378
Author(s):  
Yaqian Dong ◽  
Linna Gong ◽  
Xianyuan Lu ◽  
Mingguang Ye ◽  
Yu Lin ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Mrna Level ◽  
Hepatic Function ◽  
Clinical Findings ◽  
Drug Metabolizing Enzymes ◽  
Mrna Levels ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Metabolizing Enzymes ◽  
Adriamycin Nephropathy ◽  
Clinical Drugs

Background: Drug-metabolizing enzymes and transporters play key roles in drug disposition and drug interactions. The alterations of their expression will influence drug pharmacokinetics and pharmacodynamics. However, the changes in the expression of enzymes and transporters in the disease state are still unclear. Objective: Our study was to investigate the changes in the expression of main enzymes and drug transporters distributed in Adriamycin nephropathy rat liver, kidney, and intestine. Methods: An intravenous injection with a single dose of Adriamycin (6mg/kg) was made to establish Adriamycin nephropathy (AN) model and normal groups were injected with normal saline. Serum was collected for lipid metabolism, renal, and hepatic function measurement. The real-time PCR and western blot were applied to determine the mRNA and protein expression of drug enzymes and transporters. Results: In the kidney, a greater expression of Mdr1, Mrp2, Mrp4 Oat2 and Oct2 mRNA was found in AN rats as compared with control rats. In the liver, the expression of Bcrp mRNA was more doubled or tripled than control groups and downregulation of Mdr1, Mrp2, Mrp4 and Bsep gene expression was found in AN rats. Besides, we observed a downward trend of Cyp1a2, Cyp3a4 and Cyp2c9 mRNA levels in AN groups. In the duodenum, the expression of Mdr1 and Mrp3 mRNA level was decreased, while Bcrp and Mrp2 mRNA were increased. Conclusion: The changes in drug-metabolizing enzymes and transporters expression in AN rats were clarified, which may be beneficial for understanding the altered pharmacokinetics and pharmacodynamics of clinical drugs and reduce unexpected clinical findings for nephropathy patients.

scholarly journals Effects of Cyclamen trochopteranthum on hepatic drug-metabolizing enzymes

2011 ◽  
Vol 63 (3) ◽  
pp. 545-555 ◽  
Author(s):  
Sevki Arslan ◽  
Ozden Ozgun ◽  
Gurbet Celik ◽  
Asli Semiz ◽  
Olcay Dusen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Mrna Level ◽  
Drug Metabolizing Enzymes ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Metabolizing Enzymes ◽  
Hepatic Drug ◽  
Tuber Extract ◽  
Different Doses

The modulatory effects of the Cyclamen trochopterantum tuber extract on hepatic drug-metabolizing enzymes, including aniline 4-hydroxylase (A4H; CYP2E1), ethoxyresorufin O-deethylase (EROD; CYP1A), methoxyresorufin O-demethylase (MROD; CYP1A), caffeine N-demethylase (C3ND; CYP1A2) aminopyrene N-demethylase (APND; CYP2C6), and erythromycin N-demethylase (ERND; CYP3A1), were examined in vivo in rats. The activities of all of these enzymes were induced by the cyclamen extract. In addition, Western-blot and RT-PCR results clearly showed that CYP2E1, CYP1A1/CYP1A2 and CYP2C6 protein and mRNA levels were substantially increased by four different doses of cyclamen. Although, the CYP3A1 protein level was increased significantly, the mRNA level was not changed. These results indicate that cyclamen tuber extract might have a potential not only to inhibit and/or induce the metabolism of certain co-administered drugs but also influence the development of toxicity and carcinogenesis due to the induction of the cytochrome P450-dependent drug-metabolizing enzymes.

scholarly journals A Pilot Study towards the Impact of Type 2 Diabetes on the Expression and Activities of Drug Metabolizing Enzymes and Transporters in Human Duodenum

2019 ◽  
Vol 20 (13) ◽  
pp. 3257 ◽  
Author(s):  
Sophie Gravel ◽  
Benoit Panzini ◽  
Francois Belanger ◽  
Jacques Turgeon ◽  
Veronique Michaud
Keyword(s):  
Type 2 Diabetes ◽  
Mrna Expression ◽  
Drug Metabolizing Enzymes ◽  
Mrna Levels ◽  
Metabolizing Enzymes ◽  
Expression Levels ◽  
The Impact ◽  
Duodenal Biopsies ◽  
Mrna Expression Levels

To characterize effects of type 2 diabetes (T2D) on mRNA expression levels for 10 Cytochromes P450 (CYP450s), two carboxylesterases, and three drug transporters (ABCB1, ABCG2, SLCO2B1) in human duodenal biopsies. To compare drug metabolizing enzyme activities of four CYP450 isoenzymes in duodenal biopsies from patients with or without T2D. mRNA levels were quantified (RT-qPCR) in human duodenal biopsies obtained from patients with (n = 20) or without (n = 16) T2D undergoing a scheduled gastro-intestinal endoscopy. CYP450 activities were determined following incubation of biopsy homogenates with probe substrates for CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2J2 (ebastine), and CYP3A4/5 (midazolam). Covariables related to inflammation, T2D, demographic, and genetics were investigated. T2D had no major effects on mRNA levels of all enzymes and transporters assessed. Formation rates of metabolites (pmoles mg protein−1 min−1) determined by LC-MS/MS for CYP2C9 (0.48 ± 0.26 vs. 0.41 ± 0.12), CYP2J2 (2.16 ± 1.70 vs. 1.69 ± 0.93), and CYP3A (5.25 ± 3.72 vs. 5.02 ± 4.76) were not different between biopsies obtained from individuals with or without T2D (p > 0.05). No CYP2B6 specific activity was measured. TNF-α levels were higher in T2D patients but did not correlate with any changes in mRNA expression levels for drug metabolizing enzymes or transporters in the duodenum. T2D did not modulate expression or activity of tested drug metabolizing enzymes and transporters in the human duodenum. Previously reported changes in drug oral clearances in patients with T2D could be due to a tissue-specific disease modulation occurring in the liver and/or in other parts of the intestines.

scholarly journals The reference liver—CYP450 and UGT enzymes in healthy donor and metastatic livers: the impact of genotype

2021 ◽  
Author(s):  
Mateusz Kurzawski ◽  
Sylwia Szeląg-Pieniek ◽  
Joanna Łapczuk-Romańska ◽  
Maciej Wrzesiński ◽  
Stefan Oswald ◽  
...  
Keyword(s):  
Protein Content ◽  
Mrna Level ◽  
Inverse Correlation ◽  
Control Group ◽  
Drug Metabolizing Enzymes ◽  
Protein Abundance ◽  
Metabolizing Enzymes ◽  
Functional Variants ◽  
Common Genetic Variants ◽  
The Impact

Abstract Background Hepatic enzymes involved in drug metabolism vary markedly in expression, abundance and activity, which affects individual susceptibility to drugs and toxicants. The present study aimed to compare mRNA expression and protein abundance of the most pharmacologically relevant drug-metabolizing enzymes in two main sources of the control liver samples that are used as the reference, i.e. organ donor livers and non-tumorous tissue from metastatic livers. An association analysis of the most common genetic variants with mRNA and protein levels was also performed. Methods The CYP450 and UGT enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, UGT1A1, UGT1A3, UGT2B7 and UGT2B15) were analyzed for mRNA (qPCR) and protein abundance (LC–MS/MS) in healthy donors (n = 11) and metastatic (n = 13) livers. Genotyping was performed by means of TaqMan assays and pyrosequencing. Results Significantly higher protein abundance in the metastatic livers was observed in case of CYP2C9, CYP2D6, and UGT2B7, and for UGT1A3 the difference was only significant at mRNA level. For all the enzymes except CYP2E1 some significant correlation between mRNA and protein content was observed, and for UGT1A1 an inverse correlation with age was noted. CYP2C19, CYP3A5 and CYP2D6 were significantly affected by genotype. Conclusion The selection of a control group for the study on drug-metabolizing enzymes (e.g. in pathological states) may possibly affect its conclusions on differences in mRNA and protein content. Genotyping for common functional variants of CYP450 enzymes should be performed in all studies on drug-metabolizing enzymes.

A pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer (AIPC) using targeted human DMET genotyping platform

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3580-3580
Author(s):  
J. F. Deeken ◽  
T. Cormier ◽  
D. K. Price ◽  
S. Steinberg ◽  
K. Tran ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase Ii ◽  
Drug Disposition ◽  
Individual Variability ◽  
Response To Therapy ◽  
Drug Metabolizing Enzymes ◽  
Nucleotide Polymorphisms ◽  
Pharmacogenetic Study ◽  
Metabolizing Enzymes ◽  
Genotyping Platform

3580 Background: Pharmacogenetic research holds the promise of individualizing cancer therapy by reducing inter-individual variability in drug response, thus enhancing efficacy and reducing toxicity. Past research has been limited due to the lack of a robust genotyping platform that can screen for single nucleotide polymorphisms (SNPs) in the dozens of genes known to be involved in drug disposition. We pilot tested the new Affymetrix Targeted Human Drug Metabolizing Enzymes and Transporter (DMET) 1.0 panel in an exploratory study of docetaxel and thalidomide. The DMET 1.0 panel tests for 1,229 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. Methods: DNA samples from 47 patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DMET 1.0 panel. Patients’ response was determined using RECIST criteria. Toxicities were graded using the NCI-CTC, and patients were identified if they experienced grade 3 or 4 toxicity. Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. An association between the SNP parameters and clinical response or toxicity was tested using Mehta’s modification to Fisher’s exact test. Reported results were limited to those where p<0.01. Results: Six SNPs in three genes were associated with response to therapy: PPAR-delta (p=0.0011), SULT1C2 (p=0.0083), and CHST3 (4 SNPs, p=0.0001 to 0.0034). For toxicities associated with docetaxel, five SNPs in three genes were identified: UGT1A1 (2 SNPs, p=0.0009 to 0.0094), UGT1A9 (2 SNPs, p=0.0016 to 0.0096), and CYP2A7 (p=0.0027). SNPs in CYP2B6 (p=0.0033), ABCC1 (p=0.0036), and ABCC6 (p=0.0075) were associated with toxicities from thalidomide. Conclusion: We identified nine genes in which SNPs were potentially significantly associated with clinical response and toxicity to treatment. These results highlight the important role that non-CYP450 and phase II drug metabolizing enzymes may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted. No significant financial relationships to disclose.

scholarly journals Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability

2015 ◽  
Vol 465 (3) ◽  
pp. 479-488 ◽  
Author(s):  
Colin J. Henderson ◽  
Lesley A. McLaughlin ◽  
Maria Osuna-Cabello ◽  
Malcolm Taylor ◽  
Ian Gilbert ◽  
...  
Keyword(s):  
Mouse Model ◽  
Oral Bioavailability ◽  
Drug Disposition ◽  
Single Agent ◽  
Cre Recombinase ◽  
Drug Metabolizing Enzymes ◽  
Relative Role ◽  
Metabolizing Enzymes ◽  
Gut Metabolism

We describe a mouse model where the functions of key drug-metabolizing enzymes are deleted in liver or liver and gut by application of a single agent, allowing the relative role of each tissue in drug disposition to be established.

Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics

Science ◽  
1999 ◽  
Vol 286 (5439) ◽  
pp. 487-491 ◽  
Author(s):  
William E. Evans ◽  
Mary V. Relling
Keyword(s):  
Drug Therapy ◽  
Drug Discovery ◽  
Drug Targets ◽  
Drug Disposition ◽  
Scientific Basis ◽  
Genetic Constitution ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Interindividual Differences ◽  
Pharmacogenomic Studies

Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. Pharmacogenomic studies are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby enhancing drug discovery and providing a stronger scientific basis for optimizing drug therapy on the basis of each patient's genetic constitution.

scholarly journals Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD2 in the kidney

2021 ◽  
Vol 25 (5) ◽  
pp. 445-455
Author(s):  
Naohiro Takahashi ◽  
Hiroaki Kikuchi ◽  
Ayaka Usui ◽  
Taisuke Furusho ◽  
Takuya Fujimaru ◽  
...  
Keyword(s):  
Type I Collagen ◽  
Interstitial Fibrosis ◽  
Mrna Level ◽  
Type I ◽  
Renal Tubules ◽  
Mrna Levels ◽  
Metabolizing Enzymes ◽  
Protein Levels ◽  
Lipid Metabolizing Enzymes

Abstract Background Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. Methods To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. Results In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15−/− mice. Alox15−/− CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15−/− CKD mice. Mediator lipidomics revealed that Alox15−/− CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. Conclusion Increased PGD2 in Alox15−/− CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.

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