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
Source: PubMed


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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    • "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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