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Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats.

Lu X, Hu B, Zheng J, Ji C, Fan X, Gao Y - PLoS ONE (2015)

Bottom Line: In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI), the changes of these genes' expression posterior to APAP treatment were detected.Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals.In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

ABSTRACT
The extent of drug-induced liver injury (DILI) can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP) as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI), the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI.

No MeSH data available.


Related in: MedlinePlus

Comparison of the serum ALT, AST, and TBILI levels between predicted susceptible and resistant groups selected by predose expression levels of Incenp, Rpgrip1, Mmp12, and Sbf1 in precollected blood samples prior to APAP administration in the new set of 32 rats.The 8 rats had lowest gene expression levels of 32 rats were predicted to susceptible group, whereas 8 rats had highest gene expression levels of 32 rats were predicted to resistant group. (A) Incenp, (B) Rpgrip1, (C) Mmp12, and (D) Sbf1. Values are represented as mean ± SD. * p < 0.05, ** p < 0.01 compared with resistant group.
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pone.0141750.g005: Comparison of the serum ALT, AST, and TBILI levels between predicted susceptible and resistant groups selected by predose expression levels of Incenp, Rpgrip1, Mmp12, and Sbf1 in precollected blood samples prior to APAP administration in the new set of 32 rats.The 8 rats had lowest gene expression levels of 32 rats were predicted to susceptible group, whereas 8 rats had highest gene expression levels of 32 rats were predicted to resistant group. (A) Incenp, (B) Rpgrip1, (C) Mmp12, and (D) Sbf1. Values are represented as mean ± SD. * p < 0.05, ** p < 0.01 compared with resistant group.

Mentions: Then, by measuring the levels of serum biochemical parameters after APAP treatment, the actual susceptibility to AILI was determined. As a result, the 8 predicted susceptible rats with lower expression levels in the two genes, Incenp and Rpgrip1, showed significant higher ALT, AST and/or TBILI levels than predicted resistant animals, while for the other two genes, Mmp12 and Sbf1, the trend was the same, but no significant differences were detected between these two predicted sub-groups (Fig 5, the data of ALP were not shown, because there were no difference detected between the two sub-groups). The results of histopathological examinations also showed that necrosis and inflammatory cell infiltration were detected in all the rats of predicted susceptible group, whereas hydropic degeneration of hepatocytes were observed in all the rats of predicted resistant group (Fig 6). Furthermore, based on the levels of serum biochemical parameters, ALT, AST, ALP, and TBILI, five most susceptible and the five most resistant rats were selected, respectively. As shown in Fig 7, the expression levels of the four genes showed differences between the two sub-groups in the selected rats based on the serum biochemical parameters, and the susceptible rats had the lower gene expression levels than resistant rats, especially selected by ALT and/or AST in Incenp and Rpgrip1, which was in good agreement with microarray and predicted results.


Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats.

Lu X, Hu B, Zheng J, Ji C, Fan X, Gao Y - PLoS ONE (2015)

Comparison of the serum ALT, AST, and TBILI levels between predicted susceptible and resistant groups selected by predose expression levels of Incenp, Rpgrip1, Mmp12, and Sbf1 in precollected blood samples prior to APAP administration in the new set of 32 rats.The 8 rats had lowest gene expression levels of 32 rats were predicted to susceptible group, whereas 8 rats had highest gene expression levels of 32 rats were predicted to resistant group. (A) Incenp, (B) Rpgrip1, (C) Mmp12, and (D) Sbf1. Values are represented as mean ± SD. * p < 0.05, ** p < 0.01 compared with resistant group.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4626237&req=5

pone.0141750.g005: Comparison of the serum ALT, AST, and TBILI levels between predicted susceptible and resistant groups selected by predose expression levels of Incenp, Rpgrip1, Mmp12, and Sbf1 in precollected blood samples prior to APAP administration in the new set of 32 rats.The 8 rats had lowest gene expression levels of 32 rats were predicted to susceptible group, whereas 8 rats had highest gene expression levels of 32 rats were predicted to resistant group. (A) Incenp, (B) Rpgrip1, (C) Mmp12, and (D) Sbf1. Values are represented as mean ± SD. * p < 0.05, ** p < 0.01 compared with resistant group.
Mentions: Then, by measuring the levels of serum biochemical parameters after APAP treatment, the actual susceptibility to AILI was determined. As a result, the 8 predicted susceptible rats with lower expression levels in the two genes, Incenp and Rpgrip1, showed significant higher ALT, AST and/or TBILI levels than predicted resistant animals, while for the other two genes, Mmp12 and Sbf1, the trend was the same, but no significant differences were detected between these two predicted sub-groups (Fig 5, the data of ALP were not shown, because there were no difference detected between the two sub-groups). The results of histopathological examinations also showed that necrosis and inflammatory cell infiltration were detected in all the rats of predicted susceptible group, whereas hydropic degeneration of hepatocytes were observed in all the rats of predicted resistant group (Fig 6). Furthermore, based on the levels of serum biochemical parameters, ALT, AST, ALP, and TBILI, five most susceptible and the five most resistant rats were selected, respectively. As shown in Fig 7, the expression levels of the four genes showed differences between the two sub-groups in the selected rats based on the serum biochemical parameters, and the susceptible rats had the lower gene expression levels than resistant rats, especially selected by ALT and/or AST in Incenp and Rpgrip1, which was in good agreement with microarray and predicted results.

Bottom Line: In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI), the changes of these genes' expression posterior to APAP treatment were detected.Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals.In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI.

View Article: PubMed Central - PubMed

Affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

ABSTRACT
The extent of drug-induced liver injury (DILI) can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP) as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI), the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI.

No MeSH data available.


Related in: MedlinePlus