Expression levels of pituitary tumor transforming 1 and glutathione-S-transferase theta 3 are associated with the individual susceptibility to D-galactosamine-induced hepatotoxicity.
ABSTRACT Although drug-induced liver injury (DILI) is frequently observed, individual variation in the susceptibility to DILI is hard to predict. Intrinsic genetic variation is considered a key element for this variation but little is known about the identity of the genes associated with DILI. In this study, pre-biopsy method was applied to uncover the key genes for D-galactosamine (GalN)-induced liver injury and a cause and effect study was conducted to elucidate the correlation between the expression of uncovered genes and GalN-induced hepatotoxicity. To identify the genes determining the susceptibility to GalN-induced hepatotoxicity, we compared the innate gene expression profiles in the liver tissue pre-biopsied before GalN treatment of the SD rats susceptible and resistant to GalN-induced hepatotoxicity, using microarray. Eight genes including Pttg1, Ifit1 and Gstt3 were lower or higher in the susceptible animals than the resistant and RT-PCR analysis confirmed it. To determine if these genes are associated with the susceptibility to GalN-induced hepatotoxicity indeed, expression levels were measured using real-time PCR in a new set of animals and the correlation with GalN-induced hepatotoxicity were analyzed. Notably, the expression of Pttg1 was significantly correlated with the severity of GalN-induced hepatotoxicity (p<0.01) and the animals with lowest and highest level of Gstt3 turned out to be the most susceptible and resistant, respectively, demonstrating that the expression of Pttg1 and Gstt3 could predict inter-individual susceptibility to GalN-induced hepatotoxicity. More importantly, this study showed the utility of pre-biopsy method in the identification of the gene for the chemical-induced hepatotoxicity.
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ABSTRACT: The underlying need for glutathione S-transferase (Gst) induction is thought to be an adaptive response to chemical stress within the cell. Classical microsomal enzyme inducers (MEIs) increase the expression of biotransformation enzymes (phase I and II) and transporters through transcription factors, such as the aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor (PPAR) alpha, and nuclear factor erythroid-derived 2-related factor 2 (Nrf2). The effects of MEIs on the induction of hepatic Gsts in mice have not been comprehensively characterized. The purpose of this study was to determine the effects of 15 MEIs on the mRNA expression of 19 mouse Gsts. Male C57BL/6 mice were treated with three different activators each for AhR, CAR, PXR, PPARalpha, and Nrf2. In general, the Gsts are readily induced. All five transcription factors appear to play a role in Gst induction. The Nrf2 activators induced most Gsts (10), followed by the CAR, PXR, and PPARalpha activators (6-7), whereas the AhR ligands induced the least (1). Clofibrate, a PPARalpha agonist, induced most of the Gsts; however, all three PPARalpha agonists decreased Gstp1/2 mRNA. None of the 15 inducers was able to increase or only minimally increased eight of the Gsts (Gsta3, Gstk1, Gstm6, Gsto1, Gstp1/2, Gstt3, Gstz1, and MGst1). Thus, the protection afforded by a ligand for one of these transcription factors will depend on the activator, as well as which Gst that detoxifies the chemicals of interest.Toxicological Sciences 09/2008; 106(2):329-38. · 4.33 Impact Factor
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ABSTRACT: We investigated the hepatoprotective effect of purple potato extract (PPE) against D-galactosamine (GalN)-induced liver injury in rats. PPE (400 mg) was administered once daily for 8 d, and then GalN (250 mg/kg of body weight) was injected at 22 h before the rats were killed. Serum tumor necrosis factor alpha (TNF-alpha), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and asparate aminotranferase (AST) levels increased significantly after injection of GalN, but PPE inhibited GalN-induced alterations in serum TNF-alpha, LDH, ALT, and AST levels. Hepatic lipid peroxide and glutathione levels in the control + GalN group were higher and lower respectively than those in the control group, and those in the PPE + GalN group did not differ from that in the control group. The lipid peroxide level in hepatic microsomes treated with 2,2'-azobis (2-amidinopropane) dihydrochloride in the PPE group was significantly lower than that in the control group. This suggests that PPE has hepatoprotective effects against GalN-induced hepatotoxicity via inhibition lipid peroxidation and/or inflammation in rats.Bioscience Biotechnology and Biochemistry 07/2006; 70(6):1432-7. · 1.27 Impact Factor
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ABSTRACT: Drug-induced liver disease (DILD) continues to cause significant morbidity and mortality and impair new drug development. Mounting evidence suggests that DILD is a complex, multifactorial disease in which no one factor is likely to be an absolute indicator of susceptibility. As an approach to better understand the multifactorial basis of DILD, we recently compared the hepatic proteomes of mice that were resistant (SJL) and susceptible (C57Bl/6) to APAP-induced liver disease (AILD) wherein we identified potential risk factors and mechanistic pathways responsible for DILD. In this study, we have uncovered additional potential risk factors by comparing hepatic mRNA expression profiles of the same two strains of mice with that of SJLxB6-F1 hybrid (F1) mice, which were found to be of intermediate susceptibility to AILD. Global hepatic gene expression profiling over a 24 h period following APAP treatment revealed elevated patterns in the mRNA expression of cytoprotective genes in resistant SJL mice as compared to susceptible B6 mice, while F1 mice had intermediate mRNA expression levels of these genes. One of these genes encoded for heat shock protein (HSP) 70 whose relative protein expression among the three strains of mice was found to parallel that of their mRNA levels, suggesting that this protein had a protective role against AILD. However, there was no difference in the susceptibility of HSP70 knockout (KO) mice to AILD as compared to wild-type (WT) mice. There were also protoxicant genes, such as osteopontin (OPN), with elevated mRNA expression levels in the B6 mice as compared to the SJL mice and with intermediate levels in the F1 mice, suggesting that they may play a role in exacerbating liver injury after APAP treatment. In support of this hypothesis, OPN KO mice were found to be more resistant to AILD than WT mice. Additionally, the results from both the proteomic and the genomic studies were compared. The two approaches were found to be complementary to each other and not simply overlapping. Our findings suggest that comparative gene expression analysis of susceptible and resistant mouse strains may lead to the identification of factors that could have a role in determining the susceptibility of individuals to DILD.Chemical Research in Toxicology 03/2006; 19(2):223-33. · 3.67 Impact Factor