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

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.

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

“…Adaptive tolerance, or resistance to APAP toxicity that occurs following “pre-exposure” to APAP, is believed to occur in humans and experimental animals exposed to APAP over a long time period (Eakins et al 2015; O’Brien et al 2000; Shayiq et al 1999). The molecular mechanisms underlying adaptive tolerance are not well understood.…”

From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective

“…On the contrary, the induction of FMO3 is not regulated by Nrf2 30 . Furthermore, deletion of Nrf2 alone does not abolish APAP autoprotection, since Nrf2-null mice develop tolerance to APAP hepatotoxicity similar to wild-type mice ( 14 and unpublished data from our laboratory). This is a critical observation, since two independent studies suggest that Nrf2 response likely contributes to APAP autoprotection, yet a gene loss-of-function approach demonstrated that Nrf2 response is not a prerequisite for APAP autoprotection.…”

“…Although we showed that pretreatment alone does not alter cellular GSH levels or decrease CYP enzymes that metabolize APAP, a recent study by Eakins et al showed that in APAP autoprotected livers, there is higher GSH-mediated detoxification of APAP and changes in localization of one of the CYP isoenzymes that metabolizes APAP to its toxic intermediate. They noted periportal expression of CYP2E1 in autoprotected livers as opposed to its normal centrilobular expression 14 . The functional consequence of this change in enzyme localization is not currently known.…”

“…More recently, Eakins et al also addressed this subject through proteomic analysis in another rodent model of APAP autoprotection involving repeated APAP administration every 24 hours for up to 96 hours 14 . The gene array analysis performed by our group in our APAP autoprotection model identified many differentially expressed genes that could contribute to the development of resistance to APAP hepatotoxicity upon re-exposure to this toxicant.…”

Novel circulating- and imaging-based biomarkers to enhance the mechanistic understanding of human drug-induced liver injury

“…The liver is one of the most complex organs in our bodies and its capacity of adaptation and regeneration to toxic challenges or surgery has widely been studied [85]. As previously mentioned, we tend to focus on liver injury and cell death forgetting about the remaining functional parenchyma.…”