Effect of acetaminophen on expression and activity of rat liver multidrug resistance-associated protein 2 and P-glycoprotein

Ghanem, Carolina Inés; Gómez, Paula C.; Arana, María C.; Perassolo, Marı́a; Ruiz, María Laura; Villanueva, Silvina Stella Maris; Ochoa, Elena J.; Catania, Viviana A.; Bengochea, L; Mottino, Aldo D.

doi:10.1016/j.bcp.2004.05.014

Cited by 47 publications

(37 citation statements)

References 34 publications

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“…Additional efflux transport proteins that were changed in human liver include MRP5, BCRP, and P-gp. Similar to human liver, APAP exposure induced P-gp protein levels in mice (unpublished observations from our laboratory) and rats (Ghanem et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Induction of Hepatobiliary Efflux Transporters in Acetaminophen-Induced Acute Liver Failure Cases

Barnes¹,

Aleksunes²,

Augustine³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Alterations in transporter expression may represent a compensatory mechanism of damaged hepatocytes to reduce accumulation of potentially toxic compounds. The present study was conducted to investigate the expression of hepatobiliary efflux transporters in livers from patients after toxic acetaminophen (APAP) ingestion, with livers from patients with primary biliary cirrhosis (PBC) serving as positive controls. mRNA and protein expression of multidrug resistance-associated protein (MRP) 1-6, multidrug resistance protein (MDR) 1-3/P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) in normal (n ‫؍‬ 6), APAP overdose (n ‫؍‬ 5), and PBC (n ‫؍‬ 6) human liver samples were determined by branched DNA and Western blot analysis, respectively. Double immunohistochemical staining of P-gp and proliferating cell nuclear antigen (PCNA), a marker of proliferation, was performed on paraffin-embedded tissue sections. Compared with normal liver specimens, MRP1 and MRP4 mRNA levels were elevated after APAP overdose and in PBC. Up-regulation of MRP5, MDR1, and BCRP mRNA occurred in PBC livers. Protein levels of MRP4, MRP5, BCRP, and P-gp were increased in both disease states, with MRP1 and MRP3 protein also being induced in PBC. Increased P-gp protein was confirmed immunohistochemically and was found to localize to areas of PCNA-positive hepatocytes, which were detected in APAP overdose and PBC livers. The findings from this study demonstrate that hepatic efflux transporter expression is up-regulated in cases of APAP-induced liver failure and PBC. This adaptation may aid in reducing retention of byproducts of cellular injury and bile constituents within hepatocytes. The close proximity of P-gp and PCNApositive hepatocytes during liver injury suggests that along with cell regeneration, increased efflux transporter expression is a critical response to hepatic damage to protect the liver from additional insult.The incidence of acetaminophen (APAP) overdose, which frequently leads to severe liver injury at supratherapeutic doses, has been steadily increasing in the United States. The number of APAP-related cases of liver failure has increased from 39% (1998 -2001) to nearly 50% (2003) of all cases of acute liver failure, with well over 100,000 cases of APAP overdose reported annually in the United States (Lee, 2004). Although APAP poisoning is often intentional, an increased incidence of unintentional overdose cases is gaining attention. A recent study reported that 50% of APAP overdose cases were attributable to unintentional exposure, most commonly because of APAP overutilization in multiple over-the-counter and prescription preparations (Larson et al., 2005).Mouse models of APAP-induced hepatotoxicity are widely used to recapitulate human exposures because of the similarities in APAP bioactivation and patterns of liver injury between mice and humans. Similar doses of APAP cause hepatotoxicity in both species, and the liver injury is dose-dependant (Mitchell et al., 1973;Davis et al., 1974). Another striking...

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Section: Discussionmentioning

confidence: 99%

Induction of Hepatobiliary Efflux Transporters in Acetaminophen-Induced Acute Liver Failure Cases

Barnes¹,

Aleksunes²,

Augustine³

et al. 2007

Drug Metab Dispos

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“…In general, hepatobiliary transporters are similarly regulated in rodents and humans in response to APAP. Exposure of rats to APAP increases hepatic Mrp2 and Pgp protein expression (Ghanem et al, 2004). Administration of a single toxic dose of APAP to mice lowers mRNA expression of the basolateral uptake transporters Oatp1a1, Oatp1b2, and Ntcp (Aleksunes et al, 2005.…”

Section: Klaassen and Aleksunesmentioning

confidence: 97%

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

2010

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“…There were reports that multidrug resistance-associated proteins (MRPs) were expressed in the liver and could pump BBR out of cells. 18,35) Currently, there is no report whether Tet could influence the functions of MRPs. However, based on our results, we infer that Tet could not inhibit the transporters responsible for BBR efflux other than P-gp in liver cells.…”

Section: Tet Has No Effect On Glucose Metabolism In Vitromentioning

confidence: 99%

Tetrandrine Potentiates the Hypoglycemic Efficacy of Berberine by Inhibiting P-Glycoprotein Function

Shan

Zhu

Pang

et al. 2013

Biological & Pharmaceutical Bulletin

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This study was designed to improve the absorption and hypoglycemic efficacy of berberine (BBR), which is a substrate of P-glycoprotein (P-gp), by combination with a P-gp inhibitor tetrandrine (Tet). Flow cytometry and LC-MS/MS were used to determine the cellular efflux or retention of chemicals. Pharmacokinetic study was performed in ICR mice following oral administration of the study compounds. The hypoglycemic efficacies of the compounds were evaluated in diabetic KK-Ay mice. In the in vitro experiments, Tet significantly inhibited the efflux and increased the uptake of P-gp substrates rhodamine-123 as well as BBR in MCF7/DOX cells and Caco-2 intestinal cells. Meanwhile, Tet greatly reduced the expression of P-gp in Caco-2 cells. The inhibition of BBR efflux by Tet was translated into improved pharmacokinetics in vivo. When co-administered, Tet dose-dependently increased the average maximum concentration (C max ) and area under concentration-time curve (AUC 0-24 ) of BBR in mice. Tet itself had no impact on glucose metabolism. However, it greatly potentiated the hypoglycemic efficacy of BBR in diabetic KK-Ay mice. In addition, we found that Tet had moderate inhibitory effect on the catalytic activity of CYP3A4, which played a role in the bio-transformation of BBR, and this may also take part in the improvement of the pharmacokinetics of BBR. In summary, combination with P-gp inhibitors such as Tet can improve the pharmacokinetics and hypoglycemic efficacy of BBR greatly; this implicates a feasible strategy for exploring the therapeutic effects of BBR and other pharmaceuticals which are substrates of P-gp.

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Effect of acetaminophen on expression and activity of rat liver multidrug resistance-associated protein 2 and P-glycoprotein

Cited by 47 publications

References 34 publications

Induction of Hepatobiliary Efflux Transporters in Acetaminophen-Induced Acute Liver Failure Cases

Induction of Hepatobiliary Efflux Transporters in Acetaminophen-Induced Acute Liver Failure Cases

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Tetrandrine Potentiates the Hypoglycemic Efficacy of Berberine by Inhibiting P-Glycoprotein Function

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