OCT1 (SLC22A1) transporter kinetics and regulation in primary human hepatocyte 3D spheroids

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OCT1 (SLC22A1) transporter kinetics and regulation in primary human hepatocyte 3D spheroids

Mickols, Evgeniya (author): Uppsala universitet,Institutionen för farmaci

Meyer, Alina (author): Uppsala universitet,Institutionen för farmaci

Handin, Niklas (author): Uppsala universitet,Institutionen för farmaci

Stüwe, Malin (author): Uppsala universitet,Institutionen för farmaci

Eriksson, Jens, 1982- (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab

Rudfeldt, Jakob (author): Uppsala universitet,Cancerfarmakologi och beräkningsmedicin

Blom, Kristin (author): Uppsala universitet,Cancerfarmakologi och beräkningsmedicin

Fryknäs, Mårten (author): Uppsala universitet,Cancerfarmakologi och beräkningsmedicin

Sellin, Mikael E. (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi

Lauschke, Volker M. (author): Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden;Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany;University of Tübingen, Tübingen, Germany;Centre of Molecular Medicine, Karolinska Institute, Stockholm, Sweden

Karlgren, Maria (author): Uppsala universitet,Institutionen för farmaci

Artursson, Per (author): Uppsala universitet,Institutionen för farmaci

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Springer Nature, 2024
2024
English.
In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

3D spheroids of primary human hepatocytes (3D PHH) retain a differentiated phenotype with largely conserved metabolic function and proteomic fingerprint over weeks in culture. As a result, 3D PHH are gaining importance as a model for mechanistic liver homeostasis studies and in vitro to in vivo extrapolation (IVIVE) in drug discovery. However, the kinetics and regulation of drug transporters have not yet been assessed in 3D PHH. Here, we used organic cation transporter 1 (OCT1/SLC22A1) as a model to study both transport kinetics and the long-term regulation of transporter activity via relevant signalling pathways. The kinetics of the OCT1 transporter was studied using the fluorescent model substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+) and known OCT1 inhibitors in individual 3D PHH. For long-term studies, 3D PHH were treated with xenobiotics for seven days, after which protein expression and OCT1 function were assessed. Global proteomic analysis was used to track hepatic phenotypes as well as prototypical changes in other regulated proteins, such as P-glycoprotein and Cytochrome P450 3A4. ASP+ kinetics indicated a fully functional OCT1 transporter with a Km value of 14 ± 4.0µM as the mean from three donors. Co-incubation with known OCT1 inhibitors decreased the uptake of ASP+ in the 3D PHH spheroids by 35–52%. The long-term exposure studies showed that OCT1 is relatively stable upon activation of nuclear receptor signalling or exposure to compounds that could induce inflammation, steatosis or liver injury. Our results demonstrate that 3D PHH spheroids express physiologically relevant levels of fully active OCT1 and that its transporter kinetics can be accurately studied in the 3D PHH configuration. We also confirm that OCT1 remains stable and functional during the activation of key metabolic pathways that alter the expression and function of other drug transporters and drug-metabolizing enzymes. These results will expand the range of studies that can be performed using 3D PHH.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

Keyword

Hepatocyte
Liver
Uptake
ASP
OCT1
Drug transport
Drug-Drug interaction
Spheroid
3D culture
Proteomics

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By the author/editor: Mickols, Evgeniy ...; Meyer, Alina; Handin, Niklas; Stüwe, Malin; Eriksson, Jens, ...; Rudfeldt, Jakob; show more...; Blom, Kristin; Fryknäs, Mårten; Sellin, Mikael E ...; Lauschke, Volker ...; Karlgren, Maria; Artursson, Per; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Medical Biotechn ...; and Medical Biotechn ...

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By the university: Uppsala University

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