Variability in human hepatic MRP4 expression: influence of cholestasis and genotype

This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.

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“…alterations [160]. In this latter study, c.912G>T (p.L304R) and c.2269G>A (p.Q757K) were the same as in the Japanese cohort of 2002.…”

Section: Later a Study In 95 Caucasians Reported 74 Variations Includsupporting

confidence: 50%

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Stieger

Meier

2011

Pharmacogenomics

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“…Whether upregulation of Mrp4 by BSO is a direct effect, or an indirect response associated with oxidative stress due to GSH depletion, requires further investigation. MRP4 mRNA and protein expression were significantly up-regulated in liver samples from patients with cholestasis, indicating a potential role of MRP4 in protecting the liver by decreasing the intracellular accumulation of detergent-like bile acids (Gradhand et al, 2007). Hence, the protective role of BSO in trabectedin-mediated cytotoxicity may be due to increased efflux of trabectedin or toxic metabolites by Mrp4, although the affinity of trabectedin for Mrp4 is unknown.…”

Section: Discussionmentioning

confidence: 99%

Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

Lee

Leslie

Zamek‐Gliszczynski

et al. 2008

Toxicology and Applied Pharmacology

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Trabectedin is a promising anticancer agent, but dose-limiting hepatotoxicity was observed during phase I/II clinical trials. Dexamethasone (DEX) has been shown to significantly reduce trabectedinmediated hepatotoxicity. The current study was designed to assess the capability of sandwichcultured primary rat hepatocytes (SCRH) to predict the hepato-protective effect of DEX against trabectedin-mediated cytotoxicity. The role of multidrug resistance-associated protein 2 (Mrp2; Abcc2) in trabectedin hepatic disposition also was examined. In SCRH from wild-type Wistar rats, cytotoxicity was observed after 24-hr continuous exposure to trabectedin. SCRH pretreated with additional DEX (1 µM) exhibited a 2-3-fold decrease in toxicity at 100 nM and 1000 nM trabectedin. Unexpectedly, toxicity in SCRH from Mrp2-deficient (TR − ) compared to wild-type Wistar rats was markedly reduced. Depletion of glutathione from SCRH using buthionine sulfoximine (BSO) mitigated trabectedin toxicity associated with 100 nM and 1000 nM trabectedin. Western blot analysis demonstrated increased levels of CYP3A1/2 and Mrp2 in SCRH pretreated with DEX; interestingly, Mrp4 expression was increased in SCRH after BSO exposure. Trabectedin biliary recovery in isolated perfused livers from TR − rats was decreased by ~75% compared to wild-type livers. In conclusion, SCRH represent a useful in vitro model to predict the hepatotoxicity of trabectedin observed in vivo. The protection by DEX against trabectedin-mediated cytotoxicity may be attributed, in part, to enhanced Mrp2 biliary excretion and increased metabolism by CYP3A1/2. Decreased trabectedin toxicity in SCRH from TR − rats, and in SCRH pretreated with BSO, may be due to increased basolateral excretion of trabectedin by Mrp3 and/or Mrp4.

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“…Under normal physiologic conditions, the hepatic expression of MRP3 and MRP4 is low, whereas upregulation under cholestatic conditions (e.g., inhibition of BSEP, genetic BSEP variants) has been observed (Gradhand et al, 2008;Chai et al, 2012). Therefore, these basolateral proteins are hypothesized to provide a compensatory backup system for bile acid efflux from the hepatocyte into sinusoidal blood when the normal vectorial transport of bile acids from the hepatocyte into bile is compromised (Scheffer et al, 2002;Teng and Piquette-Miller, 2007;Gradhand et al, 2008;Chai et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

et al. 2013

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Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potential of drugs. The inhibitory effect of 88 drugs (100 mM) on MRP3-and MRP4-mediated substrate transport was measured in membrane vesicles. Drugs selected for investigation included 50 BSEP non-inhibitors (24 non-cholestatic; 26 cholestatic) and 38 BSEP inhibitors (16 noncholestatic; 22 cholestatic). MRP4 inhibition was associated with an increased risk of cholestatic potential among BSEP non-inhibitors. In this group, for each 1% increase in MRP4 inhibition, the odds of the drug being cholestatic increased by 3.1%. Using an inhibition cutoff of 21%, which predicted a 50% chance of cholestasis, 62% of cholestatic drugs inhibited MRP4 (P < 0.05); in contrast, only 17% of non-cholestatic drugs were MRP4 inhibitors. Among BSEP inhibitors, MRP4 inhibition did not provide additional predictive value of cholestatic potential; almost all BSEP inhibitors were also MRP4 inhibitors. Inclusion of pharmacokinetic predictor variables (e.g., maximal unbound concentration in plasma) in addition to percent MRP4 inhibition in logistic regression models did not improve cholestasis prediction. Association of cholestasis with percent MRP3 inhibition was not statistically significant, regardless of BSEP-inhibition status. Inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI.

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Variability in human hepatic MRP4 expression: influence of cholestasis and genotype

Cited by 87 publications

References 39 publications

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

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