Proteomics informed investigation of human hepatocytes and liver tissue

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Fältnamn	Indikatorer	Metadata
000		06338nam a2200589 4500
001		oai:DiVA.org:uu-446954
003		SwePub
008		210623s2021 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
020		a 9789151312477q print
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4469542 URI
024	7	a https://doi.org/10.33063/diva-4469542 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a vet2 swepub-contenttype
072	7	a dok2 swepub-publicationtype
100	1	a Handin, Niklasu Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)nikha230
245	1 0	a Proteomics informed investigation of human hepatocytes and liver tissue
264		c 2021-08-18
264	1	a Uppsala :b Acta Universitatis Upsaliensis,c 2021
300		a 63 s.
338		a electronic2 rdacarrier
490	0	a Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy,x 1651-6192 ;v 298
500		a https://doi.org/10.33063/diva-446954
520		a A successful drug needs to display beneficial absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) profile. It is therefore important to investigate these properties during the drug discovery process. The liver is of particular interest in ADME-Tox studies, as it is highly metabolically active and oral administrated drugs needs to pass the liver before reaching the systemic circulation. However, a dose of a drug that is efficacious and safe for one individual may be inefficacious or toxic, because of inter-individual variability. Therefore, it is important to investigate the ADME-Tox properties in a sufficiently large population. Investigations on ADME-Tox is usually done in in vitro cell models. Therefore, a variety of models to simulate liver functions have been developed and ranging from subcellular microsomes to complex 3D organoid cultures. This thesis investigates variability of ADME proteins in human liver tissue and in liver cell models.First, mass spectrometry based targeted proteomics was used to quantify ADME relevant proteins from 149 human liver samples. The observed inter-individual protein variability could not solely be explained by genotype. Therefore, a single transporter protein, the bile and drug transporting protein, NTCP, was investigate in detail. Non-genetic factors, e.g. smoking and alcohol consumption, and epigenetic factors such as DNA methylation, were found to contribute to the observed inter-individual variability of NTCP. Next, hepatocytes (PHH) were isolated from 54 human livers tissues and after which the hepatocytes where cryopreserved. The variable attachment efficiency of cryopreserved hepatocytes where investigated and an apoptosis inhibition protocol for restoration of attachment properties was developed. This protocol was also successfully applied to 3D cultured PHH spheroids resulting in increased ability to form 3D spheroids. The effect of culture conditions on the quality of the 3D cultures was also investigated. 3D PHH spheroids were formed and maintained in different, commonly used culture media. The spheroids were characterized by a variety of functional assays including global proteomics. The proteome analysis showed that while no epithelial to mesenchymal transitions was observed, 3D cultures maintained in fasting glucose and insulin levels resembling the in vivo situation showed a more liver-like phenotype with a high expression of ADME proteins and functional cytochrome P450 metabolism. Transporter kinetics were also investigated in the 3D cultured PHH. Finally, we investigated if global proteomics data from 56 human liver tissues could be deconvoluted to give information about the liver composition. The cell type proportions generated by deconvolution where similar to literature values. Liver samples that displayed deviating cell composition were identified. The deviating liver compositions were in agreement with clinical markers of inflammation in the patient´s blood samples and with altered extracellular matrix protein composition, comparable to that found in liver steatosis. In conclusion, this thesis have investigated variability in ADME proteins in human liver and in in vitro cultures of human hepatocytes, characterized cofounding factors for in vitro cultured hepatocytes and further extended drug disposition studies in 3D cultured hepatocytes.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
653		a human
653		a liver
653		a hepatocytes
653		a proteomics
653		a cellular stress
653		a apoptosis
653		a hepatotoxicity
653		a 3D culture
653		a spheroid
653		a drug metabolism
653		a drug toxicity
653		a drug transport
653		a Farmaceutisk vetenskap
653		a Pharmaceutical Science
700	1	a Artursson, Per,c Professoru Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab4 ths0 (Swepub:uu)perartur
700	1	a Nygren, Peter,c Professoru Uppsala universitet,Experimentell och klinisk onkologi,Cancerfarmakologi och beräkningsmedicin,Science for Life Laboratory, SciLifeLab4 ths0 (Swepub:uu)peterng
700	1	a Sjöblom, Tobias,c Professoru Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi,Klinisk och experimentell patologi4 ths0 (Swepub:uu)tobisjob
700	1	a Fryknäs, Mårten,c Docentu Uppsala universitet,Cancerfarmakologi och beräkningsmedicin4 ths0 (Swepub:uu)mafry516
700	1	a Annaert, Pieter,c Professoru Mechanistic Pharmacokinetics KU Leuven, Belgien4 opn
710	2	a Uppsala universitetb Institutionen för farmaci4 org
856	4	u https://uu.diva-portal.org/smash/get/diva2:1572477/FULLTEXT01.pdfx primaryx Raw objecty fulltext
856	4	u https://uu.diva-portal.org/smash/get/diva2:1572477/PREVIEW01.jpgx Previewy preview image
856	4	u http://uu.diva-portal.org/smash/get/diva2:1572477/FULLTEXT01
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-446954
856	4 8	u https://doi.org/10.33063/diva-446954

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