Regulation of the hepatic multidrug resistance gene expression by endotoxin and inflammatory cytokines in mice

Hartmann, Georgy; Kim, Hani; Piquette-Miller, Micheline

doi:10.1016/s0162-3109(00)00271-x

Cited by 134 publications

(102 citation statements)

References 22 publications

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“…This represents a widespread repression of drug transport within the liver with transporters mediating both uptake and efflux from the affected hepatocyte. These findings are consistent with previously reported in vitro and in vivo models of acute inflammation in which IL-6 is reported to be the major contributor to the repression of hepatic transporter mRNA expression (Siewert et al, 2000;Hartmann et al, 2001;Teng and Piquette-Miller, 2005). The mRNA expression of Mdr1a was not anticipated to be reduced, based on the findings of previous studies that report the importance of post-translational factors in Mdr1a expression (Cornwell, 1991).…”

Section: Downregulation Of Hepatic Metabolism In Malignancysupporting

confidence: 92%

“…As acute inflammation represses the expression of hepatic transporters, the expression levels of hepatic transporters in the presence of tumour-induced inflammation were determined (Hartmann et al, 2001(Hartmann et al, , 2002Lee and Piquette-Miller, 2001;Sukhai et al, 2001). The mRNA expression levels of relevant transporters were determined in mice bearing EHS sarcoma tumours and …”

Section: Regulation Of Hepatic Transporter Genes In the Presence Of Ementioning

confidence: 99%

“…Cytokines, in particular IL-6, reduce the mRNA and protein expressions of some hepatic transporters in vivo, and function in vitro (Hartmann et al, 2001;Lee and Piquette-Miller, 2001;Sukhai et al, 2001;Hartmann et al, 2002). Conversely, in tumours, studies have demonstrated an increase in the expression of some ABC superfamily transporters on tumour cells in response to IL-6, where they produce the multidrug-resistant tumour phenotype (Conze et al, 2001;Duan et al, 2002).…”

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confidence: 99%

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Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

et al. 2007

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There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.

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Section: Downregulation Of Hepatic Metabolism In Malignancysupporting

confidence: 92%

Section: Regulation Of Hepatic Transporter Genes In the Presence Of Ementioning

confidence: 99%

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confidence: 99%

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Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

et al. 2007

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“…In addition to drug metabolism, inflammatory responses also affect drug distribution and clearance through changes in drug transporters. Indeed, a down-regulation in the expression and activity of several ATP-binding cassette (ABC) drug transporters, such as P-glycoprotein (Pgp or Mdr1) and the multidrug resistance-associated proteins (Mrp) have been reported in endotoxin, cytokine, and turpentine models of inflammation (Piquette-Miller et al, 1998;Hartmann et al, 2001;Kalitsky-Szirtes et al, 2004). It has only been recognized recently that the breast cancer resistance protein (Bcrp/Abcg2), a member of the ABC superfamily of transporters, also plays an important role in drug distribution and clearance.…”

mentioning

confidence: 99%

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

Petrović

Wang²,

Piquette-Miller

2008

Drug Metab Dispos

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ABSTRACT:On average, 80% of pregnant women consume over-the-counter and/or prescription medications. The placenta is a crucial organ that can restrict fetal drug exposure. ATP-binding cassette (ABC) drug transporters play an important role in the placenta because they limit the transplacental transfer of xenobiotics. However, the impact of infection or inflammation on placental drug transporters is not well established. Thus, we examined the impact of endotoxin-induced inflammation on the placental expression of several key drug transporters in rats and its impact on fetal exposure to a drug substrate. Real-time polymerase chain reaction results demonstrated a significant time-and dose-dependent down-regulation of breast cancer resistance protein/Abcg2 mRNA in the placentas of endotoxin-treated rats with a corresponding decrease in protein levels. Likewise, the mRNA levels of several other ABC transporters (Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3) and members of the organic anion-transporting polypeptides (Slco1a4, Slco2b1, Slco4a1) were down-regulated. A biodistribution study was carried out with glyburide, a hypoglycemic sulfonylurea substrate of both ABC efflux and Oatp uptake transporters. Although administration of endotoxin resulted in comparable plasma concentrations of glyburide, a pronounced increase in the accumulation of glyburide was seen in the fetuses of endotoxin-treated rats (162% of controls, p < 0.01). Glyburide plasma protein binding was not affected by endotoxin treatment. Overall, our results demonstrated a significant reduction in the placental expression of several important drug transporters during endotoxin-induced inflammation. Alterations in glyburide distribution highlight the potential importance of both influx and efflux placental transporters in impacting fetal drug exposure.

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“…LPS treatment of mice significantly down-regulated P-gp and Mrp2, major transporters involved in disposition of clinically relevant drugs such as colchicine, verapamil, daunorubicin, cyclosporin A and the abundant food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) (Dietrich et al, 2001;Petrovic et al, 2007). LPS-treated mice had significantly lower hepatic P-gp (30% of control) and increased P-gp expression in the kidney (140% controls) (Hartmann et al, 2001;.…”

Section: Drug Transportersmentioning

confidence: 99%

Altered Drug Metabolism and Transport in Pathophysiological Conditions

Gandhi¹,

Ghose²

2012

Topics on Drug Metabolism

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Regulation of the hepatic multidrug resistance gene expression by endotoxin and inflammatory cytokines in mice

Cited by 134 publications

References 22 publications

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

Altered Drug Metabolism and Transport in Pathophysiological Conditions

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