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In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
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2006 (English)In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 36, no 9, 647-653 p.Article in journal (Refereed) Published
Abstract [en]

Backround Artemisinin (a sesquiterpene lactone endoperoxide) has become important in multi-drug treatment of malaria. There is evidence that artemisinin induces drug metabolism which could result in drug-drug interactions. The objective of this study was to characterize the inductive properties of artemisinin on drug-metabolizing cytochrome P450 (CYP450) enzymes. Materials and methods The possibility of artemisinin to induce CYP450 was studied in artemisinin-treated (orally for four days) and vehicle-treated rats using reverse transcriptase polymerase chain reaction (RT-PCR). The effect on enzymatic activities in mouse microsomes from multiple artemisinin administration (intraperitonally) to mice were also studied as well as the effect on the expression in mouse primary hepatocytes and HEK293 cells. Results Increased CYP2B1 mRNA levels in rats could be seen after artemisinin treatment as well as a weak but reproducible increase in the intensity of CYP1A2. Administration of artemisinin to mice up-regulated hepatic CYP2B10-dependent, and to a lesser extent, CYP2A5-dependent enzyme activities. In primary hepatocyte culture, artemisinin significantly increased the CYP2B10 mRNA levels whereas the CYP2A5 mRNA levels were increased to a lesser extent. No significant changes were seen in the levels of other CYP enzymes. Artemisinin was an activator of constitutive androstane receptor (CAR) but not pregnane X receptor (PXR) in HEK293 cells. Conclusions The results demonstrate that the drug exerts its effects on drug metabolism via the CAR receptor that results in up-regulation of genes such as the Cyp2b. The weaker up-regulation of CYP2A5 might also be CAR-dependent or alternatively, a consequence of artemisinin toxicity. The results of this study are of importance when predicting potential drug-drug interactions in multi-drug therapies with artemisinin.

Place, publisher, year, edition, pages
2006. Vol. 36, no 9, 647-653 p.
Keyword [en]
CAR receptor; CYP450; drug-drug interactions; induction; malaria
National Category
Family Medicine
URN: urn:nbn:se:uu:diva-90895DOI: 10.1111/j.1365-2362.2006.01700.xISI: 000239636000008OAI: oai:DiVA.org:uu-90895DiVA: diva2:163408
Available from: 2003-10-01 Created: 2003-10-01 Last updated: 2016-08-11Bibliographically approved
In thesis
1. Expression of Genes Encoding for Drug Metabolism in the Small Intestine
Open this publication in new window or tab >>Expression of Genes Encoding for Drug Metabolism in the Small Intestine
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This investigation focused on the mRNA expression of drug metabolising Cytochromes P-450 (CYP) and UDP-glucuronosyltransferases (UGT) and the transport protein P-glycoprotein (Pgp) in the small intestine of humans and rats.

The mRNA expression of the investigated genes in the human small intestine (duodenum) varies between individuals giving each one of us personal profile. In general, the most dominant forms are Pgp, CYPs 2C9, 2D6, 3A4, and UGTs 1A1, 1A10, 2B7. However, which of these is the highest expressed one varies between individuals.

The correlation in expression between some CYP forms and UGT forms respectively is relatively high, which indicates that they have some regulatory mechanisms in common. It was also shown that the mRNA expression of both CYPs and UGTs may be affected by endogenous and exogenous factors. Sex and ethnic background, affected the mRNA expression of CYP2A6 and 2E1 respectively. Commonly used drugs such as acetylsalicylicacid (ASA) and omeprazole (omep) affect CYP2A6, CYP2E1 (ASA) and CYP3A4, UGT1A4 (omep). The expression of UGT1A4 is also affected by smoking. All these factors are commonly used and can therefore lead to important drug-drug interactions.

It was also shown that the human small intestinal CYP mRNA expression pattern differs from that found in the rat. The rat CYP expression is rather constant between the different individuals, and the main rat intestinal forms are CYP1A1, CYP2C, CYP2D6 and CYP3A1. The expression is the same for females and males and no difference can be seen between the different segments of the rat small intestine. As metabolic studies have often been done with rat liver we compared the mRNA expression in the two organs. We found that the mRNA expression of 1A1 was absent in the liver and that the CYP2B1, CYP2Cs, CYP2D1 and Pgp all had a stronger mRNA expression in the small intestine compared to the liver. It is therefore important to realise that results from metabolic studies on liver may not be directly extrapolated to the small intestine.

Artemisinin is an orally used drug in multidrug treatment of malaria in Southeast Asia. It has been suggested that artemisinin can induce drug metabolism and therefore be involved in drug-drug interactions. This study shows that artemisinin induces mainly the CYP2B via nuclear receptor CAR.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 45 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 297
Pharmaceutical biochemistry, CYPs, UGTs, interindividual variation, small intestine, human, rat, artemisinin, CAR-receptor regulation, Farmaceutisk biokemi
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-3601 (URN)91-554-5753-3 (ISBN)
Public defence
2003-10-24, C8:305, BMC, Uppsala, 09:15
Available from: 2003-10-01 Created: 2003-10-01Bibliographically approved

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Simonsson, Ulrika S.H.Raffalli-Mathieu, Francoise
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