Transport deficient (TR−) hyperbilirubinemic rats are resistant to acetaminophen hepatotoxicity

Silva, Vanessa M.; Thibodeau, Michael; Chen, Chuan; Manautou, José E.

doi:10.1016/j.bcp.2005.09.024

Cited by 15 publications

(17 citation statements)

References 31 publications

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“…In addition, the expression and activity of several phase I and II metabolic enzymes that may be involved in trabectedin detoxification are modulated in TR − rats. For example, the total P450 content and activity of CYP1A1/2 and CYP2B1/2 were significantly higher in TR − compared to wild-type rats, although testosterone 6β-hydroxylation mediated by CYP3A1/2 was lower in TR − compared to wild-type rats (Newton et al, 2005;Silva et al, 2005). TR − rats exhibit up-regulated UGT1a (Johnson et al, 2006).…”

Section: Discussionmentioning

confidence: 93%

“…Since Mrp2 plays an important role in GSH biliary excretion, impaired function of Mrp2 in TR − rats has been attributed to higher hepatocellular concentrations of GSH relative to wild-type rats (Lu et al, 1996). The important role of GSH in detoxification of the reactive metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine, was demonstrated recently in TR − rats (Silva et al, 2005); TR − rats were more resistant to acetaminophen hepatotoxicity compared to wildtype rats, but this protection against acetaminophen hepatotoxicity in TR − rats was completely reversed by BSO treatment. Previous studies in cultured rat hepatocytes have documented that 200 µM BSO reduced GSH levels by 50% after 5 hr (Sinbandhit-Tricot et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 93%

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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show abstract

“…Intriguingly, Mrp2 in the canalicular transport system has an opposing effect in the APAP hepatic injury model compared with Mrp3 [14]. Apical Mrp2-deficient mice exhibited impaired excretion of conjugated APAP into the biliary tract with greater resistance to APAP toxicity than wild-type mice, and this excretion was accompanied by high levels of APAP-glucuronide in plasma [19, 38, 39]. Hence, the differential gene regulation on the Mrp family genes by Rg3 may be helpful to decrease bile excretion and facilitate basolateral excretion of NAPQI conjugates via Nrf2 activation.…”

Section: Discussionmentioning

confidence: 99%

The Amelioration of N-Acetyl-p-Benzoquinone Imine Toxicity by Ginsenoside Rg3: The Role of Nrf2-Mediated Detoxification and Mrp1/Mrp3 Transports

Gum

Cho

2013

Oxidative Medicine and Cellular Longevity

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Previously, we found that Korean red ginseng suppressed acetaminophen (APAP)-induced hepatotoxicity via alteration of its metabolic profile involving GSTA2 induction and that ginsenoside Rg3 was a major component of this gene induction. In the present study, therefore, we assessed the protective effect of Rg3 against N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolic intermediate of APAP. Excess NAPQI resulted in GSH depletion with increases in the ALT and AST activities in H4IIE cells. Rg3 pretreatment reversed GSH depletion by NAPQI. Rg3 resulted in increased mRNA levels of the catalytic and modulatory subunit of glutamate cysteine ligase (GCL), the rate-limiting steps in GSH synthesis and subsequently increased GSH content. Rg3 increased levels of nuclear Nrf2, an essential transcriptional factor of these genes. The knockdown or knockout of the Nrf2 gene abrogated the inductions of mRNA and protein by Rg3. Abolishment of the reversal of GSH depletion by Rg3 against NAPQI was observed in Nrf2-deficient cells. Rg3 induced multidrug resistance-associated protein (Mrp) 1 and Mrp3 mRNA levels, but not in Nrf2-deficient cells. Taken together, these results demonstrate that Rg3 is efficacious in protecting hepatocytes against NAPQI insult, due to GSH repletion and coordinated gene regulations of GSH synthesis and Mrp family genes by Nrf2.

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“…Although transport of AP‐conjugated metabolites has been well characterized and involves Mrps and Bcrp, identification of a transporter recognizing unmetabolized AP as a substrate, either involving cellular uptake or extrusion is lacking. Manov et al .…”

Section: Discussionmentioning

confidence: 99%

Acetaminophen Inhibits Intestinal P-Glycoprotein Transport Activity

Novak

Carpini

Ruiz

et al. 2013

Journal of Pharmaceutical Sciences

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Transport deficient (TR−) hyperbilirubinemic rats are resistant to acetaminophen hepatotoxicity

Cited by 15 publications

References 31 publications

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

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

The Amelioration of N-Acetyl-p-Benzoquinone Imine Toxicity by Ginsenoside Rg3: The Role of Nrf2-Mediated Detoxification and Mrp1/Mrp3 Transports

Acetaminophen Inhibits Intestinal P-Glycoprotein Transport Activity

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