Expression levels of pituitary tumor transforming 1 and glutathione-S-transferase theta 3 are associated with the individual susceptibility to D-galactosamine-induced hepatotoxicity.
Amorepacific CO R&D Center, Yongin 446-729, Republic of Korea. Toxicology and Applied Pharmacology
(Impact Factor: 3.71).
10/2009; 242(1):91-9. DOI: 10.1016/j.taap.2009.09.017
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.
Available from: Tae Ryong Lee
- "Through this approach, we could find that the genes associated with ''immunity and defense,'' ''lipid, fatty acid, and steroid metabolism,'' ''transport,'' and ''complement-mediated immunity'' in the liver tissue are innately lower in the susceptible animals to CCl 4 -induced hepatotoxicity (Yun et al., 2009a). And more importantly, we could demonstrate that the innate expression level of pituitary tumor transforming 1 (pttg1) and glutathione-S-transferase theta 3 (gstt3) is wellcorrelated with the individual severity of GalN-induced hepatotoxicity (Yun et al., 2009b), indicating that this approach can be practically applied to discover the genetic markers predictive of individual susceptibility and ultimately for the prescreening of the patients potentially susceptible to chemicals with hepatotoxicity before actual treatment. Despite these novel merits of prebiopsy method over conventional toxicogenomic approaches, liver prebiopsies are still too invasive and pose a significant risk to the patient (Dinkel et al., 2003; Terjung et al., 2003). "
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ABSTRACT: Although the extent of chemical-induced liver injury differs substantially from individual to individual, it is very hard to identify susceptible population priori to chemical exposure. We report here that the gene expression of the blood samples collected predose might identify the susceptible population without actual exposure to hepatotoxicant. The innate gene expressions in the blood samples collected at predose were compared using whole-genome microarray analysis and semiquantitative PCR with the extent of hepatotoxicity following the treatment of a model hepatotoxicant, carbon tetrachloride (CCl(4)) posteriori. The expression of 18 genes was found to innately differ in the blood of the susceptible animals from the resistant to CCl(4)-induced hepatotoxicity. Of these 18 genes, three genes, NADH dehydrogenase subunit 6 (ND6), transient receptor potential cation channel, subfamily C, member 6 (Trpc6), and tetraspanin 12 (Tspan12), were found to be different reproducibly in real-time PCR analysis with independent sets of animals. Of particular note, animals with the low expression level of ND6 and Tspan12 showed significantly higher susceptibility to CCl(4)-induced hepatotoxicity indeed. This study demonstrated that blood gene expression profiling might identify the susceptible individuals to chemical-induced hepatotoxicity without actual chemical exposure, providing a novel and important methodology for the prevention of drug-induced hepatotoxicity.
Toxicological Sciences 05/2010; 115(1):12-21. DOI:10.1093/toxsci/kfq037 · 3.85 Impact Factor
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ABSTRACT: The effects of betaine supplementation on D-galactosamine-induced liver injury were examined in terms of hepatic and serum enzyme activities and of the levels of glutathione and betaine-derived intermediates. The rats induced with liver injury showed marked increases in serum enzyme activity, but those receiving dietary supplementation of 1% betaine showed enzyme activity levels similar to a control group without liver injury. Administration of betaine also increased both hepatic and serum glutathione levels, even following D-galactosamine injection. The activity of glutathione-related enzymes was markedly decreased following injection of D-galactosamine, but remained comparable to that of the control group in rats receiving 1% betaine. The concentrations of hepatic S-adenosyl methionine and cysteine showed similar trends to that observed for hepatic glutathione levels. These results indicate that 1% betaine has a hepatoprotective effect by increasing hepatic and serum glutathione levels along with glutathione-related enzyme activities in rats.
Bioscience Biotechnology and Biochemistry 07/2011; 75(7):1335-41. DOI:10.1271/bbb.110105 · 1.06 Impact Factor
Available from: Young-Eun Cho
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ABSTRACT: Cisplatin is used widely for treatment of a variety of cancer diseases. Recently, however, the use of cisplatin is restricted because of its adverse effects such as hepatotoxicity. There is no study with current proteomics technology to evaluate cisplatin-induced hepatotoxicity, even if some studies have reported on the hepatotoxicity. In this study, proteomic as well as genomic analyses have been used for identification of proteins and genes that respond to cisplatin treatment in rat primary hepatocytes. To investigate the hepatotoxic effects of cisplatin, rat primary hepatocytes were treated with an IC(20) concentration for 24 h. From proteomic analysis based on label-free quantitation strategy, cisplatin induced 76 up-regulated and 19 down-regulated proteins among 325 distinct proteins. In the mRNA level, genomic analysis revealed 72 up-regulated and 385 down-regulated genes in the cisplatin-treated group. Based on these two analyses, 19 pathways were commonly altered, whereas seven pathways were identified only by proteomic analysis, and 19 pathways were identified only by genomic analysis. Overall, this study explained the mechanism of cisplatin-induced hepatotoxicity with two points of view: well known pathways including drug metabolism, fatty acid metabolism, and glycolysis/TCA cycle and little known pathways including urea cycle and inflammation metabolism, for hepatotoxicity of other toxic agents. Up-regulated proteins detected by proteomic analysis in the cisplatin-treated group: FBP1 (fructose 1,6-bisphosphatase 1), FASN (fatty acid synthase), CAT (catalase), PRDX1 (peroxiredoxin-1), HSPD1 (60-kDa heat shock protein), MDH2 (malate dehydrogenase 2), and ARG1 (arginase 1), and also down-regulated proteins in the cisplatin-treated group: TPM1 (tropomyosin 1), TPM3 (tropomyosin 3), and CTSB (cathepsin B), were confirmed by Western blot analysis. In addition, up-regulated mRNAs detected by microarray analysis in the cisplatin-treated group: GSTA2, GSTT2, YC2, TXNRD1, CYP2E1, CYP2C13, CYP2D1, ALDH17, ARG1, ARG2, and IL-6, and also down-regulated mRNAs: CYP2C12, CYP26B1, TPM1, and TPM3, were confirmed by RT-PCR analysis. In case of PRDX1, FASN, and ARG1, they were further confirmed by immunofluorescence analysis. Through the integrated proteomic and genomic approaches, the present study provides the first pathway map related to cisplatin-induced hepatotoxicity, which may provide new insight into the mechanism of hepatotoxicity.
Molecular & Cellular Proteomics 01/2012; 11(1):M111.010884. DOI:10.1074/mcp.M111.010884 · 6.56 Impact Factor
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