Regulation of metabolizing enzymes and transporters for drugs and bile salts in human and rat intestine and liver : a study with precision-cut slices

The research described in this thesis is focused on the regulation of drug metabolizing enzymes (DMEs) and drug transporters (DTs) that are involved in drug metabolism and transport as well as in bile acid synthesis, detoxification and transport in the human and rat intestine and liver. To predict drug metabolism and transport in man, animal studies are widely applied and among the rodents, the rat is the most preferred preclinical animal species used in the harmacological and toxicological evaluation of new chemical entities (NCE) in drug discovery. However interspecies differences make this extrapolation hazardous and unreliable. Moreover the expression of DMEs and DTs is subject to regulation by ligand-activated nuclear receptors (NRs), which also exhibit profound interspecies differences. The most important NRs regulating the expression of DME’s and DT’s are the pregnane X receptor (PXR), the constitutive androstane receptor (CAR), the glucocorticoid receptor (GR), the vitamin D receptor (VDR), the aryl hydrocarbon receptor (Ahr) and nuclear factor E2-related factor 2 (Nrf2).
Data on the regulation of the expression of DMEs and DTs in animals can be obtained from in vivo studies but in man in vivo data is difficult to obtain. For human studies, occasionally tissue from patients is studied but it remains undetermined to what extent confounding factors of the disease interfere with the results, and moreover secondary effects of the ligands cannot be discriminated from primary effects. Therefore in vitro methods are required to study the direct effects of drugs on the regulation of DMEs and DTs. The available in vitro methods to study the regulation of DMEs and DTs in human liver and intestine are primary cells (hepatocytes and enterocytes), and immortalized cell lines (HepG2 and Caco-2). However, the primary cells are unstable with respect to the expression of DME’s, DT’s and NRs whereas immortalized cell lines exhibit inadequate expression of DME’s, DT’s and NRs. In this thesis, precision-cut liver slices (PCLS) and the recently validated precision-cut intestinal slices (PCIS) are used as an in vitro model to study the regulation of DME’s and DT’s in rat and human intestine and liver as well as the species-specificity and inter-organ differences herein. As these functions vary along the
length of the intestine, slices were prepared from jejunum, ileum and colon.
The main focus of the thesis was on the VDR mediated effects by calcitriol (1,25(OH)2D3) and lithocholic acid (LCA) on the regulation of DME’s and DT’s. Further, to obtain more insight in the mechanism, the effects of the VDR ligands were compared with those of specific ligands for other nuclear receptors, chenodeoxycholic acid (CDCA) and GW4064 for FXR, and pregnenolone-16α carbonitrile (PCN) for PXR, budesonide (BUD) for GR and dexamethasone (DEX) for GR and PXR.

	Titel en inhoudsopgave
	Hoofdstuk 1
	Hoofdstuk 2
	Hoofdstuk 3
	Hoofdstuk 4
	Hoofdstuk 5
	Hoofdstuk 6
	Hoofdstuk 7
	Algemene discussie en conclusies
	Engelse samenvatting
	Samenvatting
	Afkortingen
	Dankwoord
	Curriculum vitae
	Prijzen
	Publicaties
	Volledige dissertatie

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