The Functional Implications of Common Genetic Variation in <i>CYP3A5</i> and <i>ABCB1</i> in Human Proximal Tubule Cells

Knops, Noël; Heuvel, Lambertus P. van den; Masereeuw, Rosalinde; Bongaers, Inge; Loor, Henriëtte de; Levtchenko, Elena

doi:10.1021/mp500590s

Cited by 30 publications

(22 citation statements)

References 49 publications

(84 reference statements)

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“…As these transporters export substances from the cell, their overexpression or upregulation attenuates renal toxicity of their substrates. Different affinities for these transporters could distinguish nephrotoxic drugs from less nephrotoxic derivatives 10,46,47 .…”

Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

“…These renal enzymes, especially CYP3A4 and CYP3A5 and UGT1A9 and UGT2B7, might facilitate drug detoxification and efflux 10,58,59 , which could lead to drug–drug interactions because substrates that inhibit these enzymes could cause other drugs to accumulate in the proximal tubule, thereby exacerbating their nephrotoxic effects 60 . In addition to their detoxifying effects, various studies have demonstrated that these enzymes can also bioactivate xenobiotics, potentially exacerbating their nephrotoxic effects 61–63 .…”

Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

“…The fact that drugs can interact with each other and/or compete for detoxification enzyme complexes further complicates screening and presents difficulties in terms of predicting which drug combinations can be safely used by a patient 7–9 . Finally, the market has failed to develop models with which to predict drug responses of individual patients, for example, owing to genetic variations in cytochrome P450 (CYP) enzymes 10 .…”

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confidence: 99%

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Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

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Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

Section: Characterization Of Cellular Modelsmentioning

confidence: 99%

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confidence: 99%

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Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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“…http:// www.lgcstandards-atcc.org/), and can be generally useful for investigating renal tubule function and toxicity in vitro (41)(42)(43)(44). For example ci-PTEC cells were used to investigate the impact of CYP3A5 and P-glycoprotein (P-gp/MDR1, ABCB1) genetic variation on tacrolimus metabolism, which could allow mechanistic insights into nephrotoxicity associated with this calcineurin inhibitor (44).…”

Section: Kidney Slicesmentioning

confidence: 99%

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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ABSTRACT.The programme for the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25-29 October 2015) included a sunrise session presenting an overview of the state-of-the-art tools for in vitro-in vivo extrapolation (IVIVE) and mechanistic prediction of renal drug disposition. These concepts are based on approaches developed for prediction of hepatic clearance, with consideration of scaling factors physiologically relevant to kidney and the unique and complex structural organisation of this organ. Physiologically relevant kidney models require a number of parameters for mechanistic description of processes, supported by quantitative information on renal physiology (system parameters) and in vitro/in silico drug-related data. This review expands upon the themes raised during the session and highlights the importance of high quality in vitro drug data generated in appropriate experimental setup and robust system-related information for successful IVIVE of renal drug disposition. The different in vitro systems available for studying renal drug metabolism and transport are summarised and recent developments involving state-of-the-art technologies highlighted. Current gaps and uncertainties associated with system parameters related to human kidney for the development of physiologically based pharmacokinetic (PBPK) model and quantitative prediction of renal drug disposition, excretion, and/or metabolism are identified.

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“…The CYP3A4 SNP rs2740574 (also referred to as CYP3A4*1B, by The Human Cytochrome P450 (CYP) Allele Nomenclature Database, http://www.cypalleles.ki.se/) is a change in the promoter region that can potentially give higher expression levels of CYP3A4 (Lamba et al, 2002). CYP3A5 rs776746 SNP (CYP3A5*3A) encodes a truncated mRNA transcript, resulting in no protein expression (Knops et al, 2015). CYP3A7 rs2257401 (CYP3A7*2) is a non-synonymous coding SNP that yields an enzyme with increased catalytic efficiency (Rodriguez-Antona et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

CYP3A genes and the association between prenatal methylmercury exposure and neurodevelopment

Llop

Tran

Ballester

et al. 2017

Environment International

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Background Results on the association between prenatal exposure to methylmercury (MeHg) and child neuropsychological development are heterogeneous. Underlying genetic differences across study populations could contribute to this varied response to MeHg. Studies in Drosophila have identified the cytochrome p450 3A (CYP3A) family as candidate MeHg susceptibility genes. Objectives We evaluated whether genetic variation in CYP3A genes influences the association between prenatal exposure to MeHg and child neuropsychological development. Methods The study population included 2639 children from three birth cohort studies: two subcohorts in Seychelles (SCDS) (n =1160, 20 and 30 months of age, studied during the years 2001–2012), two subcohorts from Spain (INMA) (n=625, 14 months of age, 2003–2009), and two subcohorts from Italy and Greece (PHIME) (n=854, 18 months of age, 2006–2011). Total mercury, as a surrogate of MeHg, was analysed in maternal hair and/or cord blood samples. Neuropsychological development was evaluated using Bayley Scales of Infant Development (BSID). Three functional polymorphisms in the CYP3A family were analysed: rs2257401 (CYP3A7), rs776746 (CYP3A5), and rs2740574 (CYP3A4). Results There was no association between CYP3A polymorphisms and cord mercury concentrations. The scores for the BSID mental scale improved with increasing cord blood mercury concentrations for carriers of the most active alleles (β[95%CI]:=2.9[1.53,4.27] for CYP3A7 rs2257401 GG+GC, 2.51[1.04,3.98] for CYP3A5 rs776746 AA+AG and 2.31[0.12,4.50] for CYP3A4 rs2740574 GG+AG). This association was near the null for CYP3A7 CC, CYP3A5 GG and CYP3A4 AA genotypes. The interaction between the CYP3A genes and total mercury was significant (p<0.05) in European cohorts only. Conclusions Our results suggest that the polymorphisms in CYP3A genes may modify the response to dietary MeHg exposure during early life development.

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The Functional Implications of Common Genetic Variation in CYP3A5 and ABCB1 in Human Proximal Tubule Cells

Cited by 30 publications

References 49 publications

Advances in predictive in vitro models of drug-induced nephrotoxicity

Advances in predictive in vitro models of drug-induced nephrotoxicity

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

CYP3A genes and the association between prenatal methylmercury exposure and neurodevelopment

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