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Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome.

Eakins R, Walsh J, Randle L, Jenkins RE, Schuppe-Koistinen I, Rowe C, Starkey Lewis P, Vasieva O, Prats N, Brillant N, Auli M, Bayliss M, Webb S, Rees JA, Kitteringham NR, Goldring CE, Park BK - Sci Rep (2015)

Bottom Line: Acetaminophen overdose is the leading cause of acute liver failure.Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation.These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.

ABSTRACT
Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.

No MeSH data available.


Related in: MedlinePlus

Analysis of the rat liver proteome reveals widespread pathway changes in response to repeat acetaminophen exposure.Ingenuity pathway analysis showing the top twenty-five most perturbed canonical pathways during the process of adaptation to APAP exposure. The left panel shows the significance of increased abundance proteins and the right panel show significance of reduced abundance proteins. The final column denotes the number of unique proteins identified per canonical pathway. Lists are shown in Supplementary Table 3. Values in red are significant with colour intensity proportional to significance.
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f3: Analysis of the rat liver proteome reveals widespread pathway changes in response to repeat acetaminophen exposure.Ingenuity pathway analysis showing the top twenty-five most perturbed canonical pathways during the process of adaptation to APAP exposure. The left panel shows the significance of increased abundance proteins and the right panel show significance of reduced abundance proteins. The final column denotes the number of unique proteins identified per canonical pathway. Lists are shown in Supplementary Table 3. Values in red are significant with colour intensity proportional to significance.

Mentions: Ingenuity pathway analysis identified the top twenty-five most perturbed canonical pathways during the process of adaptation to APAP (Fig. 3, a full list of proteins is shown in Supplementary Table 3). The changes highlight alterations in pathways that could be anticipated in our model, e.g. NFE2L2-mediated oxidative stress response and the acute phase response and others that were unexpected, e.g. melatonin degradation and dopamine degradation. This indicates, on a pathway-scale, that autoprotection to APAP involves a range of liver processes that are much more diverse than previously recognised.


Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome.

Eakins R, Walsh J, Randle L, Jenkins RE, Schuppe-Koistinen I, Rowe C, Starkey Lewis P, Vasieva O, Prats N, Brillant N, Auli M, Bayliss M, Webb S, Rees JA, Kitteringham NR, Goldring CE, Park BK - Sci Rep (2015)

Analysis of the rat liver proteome reveals widespread pathway changes in response to repeat acetaminophen exposure.Ingenuity pathway analysis showing the top twenty-five most perturbed canonical pathways during the process of adaptation to APAP exposure. The left panel shows the significance of increased abundance proteins and the right panel show significance of reduced abundance proteins. The final column denotes the number of unique proteins identified per canonical pathway. Lists are shown in Supplementary Table 3. Values in red are significant with colour intensity proportional to significance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660393&req=5

f3: Analysis of the rat liver proteome reveals widespread pathway changes in response to repeat acetaminophen exposure.Ingenuity pathway analysis showing the top twenty-five most perturbed canonical pathways during the process of adaptation to APAP exposure. The left panel shows the significance of increased abundance proteins and the right panel show significance of reduced abundance proteins. The final column denotes the number of unique proteins identified per canonical pathway. Lists are shown in Supplementary Table 3. Values in red are significant with colour intensity proportional to significance.
Mentions: Ingenuity pathway analysis identified the top twenty-five most perturbed canonical pathways during the process of adaptation to APAP (Fig. 3, a full list of proteins is shown in Supplementary Table 3). The changes highlight alterations in pathways that could be anticipated in our model, e.g. NFE2L2-mediated oxidative stress response and the acute phase response and others that were unexpected, e.g. melatonin degradation and dopamine degradation. This indicates, on a pathway-scale, that autoprotection to APAP involves a range of liver processes that are much more diverse than previously recognised.

Bottom Line: Acetaminophen overdose is the leading cause of acute liver failure.Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation.These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.

View Article: PubMed Central - PubMed

Affiliation: MRC Centre for Drug Safety Science, University of Liverpool, Liverpool L69 3GE, UK.

ABSTRACT
Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.

No MeSH data available.


Related in: MedlinePlus