Aldo-keto reductase-7A protects liver cells and tissues from acetaminophen-induced oxidative stress and hepatotoxicity

Ahmed, Munzir M. E.; Wang, Tao; Luo, Yu; Ye, Shuilong; Wu, Qian; Guo, Zongsheng; Roebuck, Bill D.; Sutter, Thomas R.; Yang, James Y.

doi:10.1002/hep.24493

Cited by 48 publications

(31 citation statements)

References 49 publications

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“…We previously demonstrated in APAP-induced hepatotoxicity that overexpression of aldo-keto reductase-7a (AKR7A) in HepG2 caused significant hepatoprotection against APAP-induced oxidative stress and cell death [14]. In the present study, we have shown that APAP-induced hepatotoxicity and increased expression levels of aldose reductase in AML-12, and plasmid overexpressing aldose reductase augmented APAP induced oxidative stress and cell death.…”

Section: Discussionsupporting

confidence: 54%

“…Moreover, inhibition of aldose reductase renders J774A.1 macrophage cell line more susceptible to acrolein or hydrogen peroxide-induced cell death [17]. Also we previously demonstrated that increased AKR7A3 in HepG2 cells was associated with the up-regulation of oxidative stress-related enzymes to enhance cellular antioxidant defense, which appeared to contribute significantly to protection against APAP-induced toxicity [14]. Therefore, we suggest that aldose reductase may provide a mechanism for the cellular detoxification of APAP.…”

Section: Discussionmentioning

confidence: 68%

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Overexpression of Aldose Reductase Render Mouse Hepatocytes More Sensitive to Acetaminophen Induced Oxidative Stress and Cell Death

Ahmed

Al-Obosi²,

Osman

et al. 2015

Ind J Clin Biochem

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Acetaminophen (APAP) a commonly used drug for decrease the fever and pain but is capable to induced hepatotoxicity at over dose. This study was carried out to investigate the effect of APAP on the expression of antiapoptotic and antioxidative defense genes, and whether aldose reductase over-expressing plasmid capable to protect against APAP-induced oxidative stress and cell death. APAP treatment induced oxidative stress and hepatotoxicity, and significantly increased aldose reductase mRNA and protein expression in mouse hepatocyte (AML-12).Unexpectedly, AML-12 cells over-expressing aldose reductase augmented APAP-induced reduction in cell viability, reactive oxygen species (ROS) production, glutathione (GSH) depletion and glutathione S-transferase A2 expression. Moreover, over-expression of aldose reductase potentiated APAP induced reduction on proliferating cell nuclear antigen, B cell lymphoma-extra large (bcl-x L ), catalase, glutathione peroxidase-1 (GPx-1) and abolished APAP-induced B-cell lymphoma 2 (bcl-2) inductions. Further, over-expression of aldose reductase significantly abolished AMP activated protein kinase (AMPK) activity in APAP-treated cells and induced p53 expression. This results demonstrate that APAP induced toxicity in AML-12, increased aldose reductase expression, and over-expression of aldose reductase render this cell more susceptible to APAP induced oxidative stress and cell death, this probably due to inhibition AMPK or bcl-2 activity, or may due to competition between aldose reductase and glutathione reductase for NADPH.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 68%

Overexpression of Aldose Reductase Render Mouse Hepatocytes More Sensitive to Acetaminophen Induced Oxidative Stress and Cell Death

Ahmed

Al-Obosi²,

Osman

et al. 2015

Ind J Clin Biochem

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“…39,46 The human AKR genes AKR1B1 , AKR1B10 , AKR1C1 , AKR1C2 , AKR1C3 , AKR7A2 , and AKR7A3 are all regulated by the Keap1/Nrf2 system. 7,9,10,47–52 Although many studies measure NQO1 induction as a read out of Nrf2 activation, often the level of induction of NQO1 is a quite modest 2–3 fold by comparison to the induction seen in the AKR genes, which can be 1–2 orders of magnitude greater. 52,53 In fact, the AKR gene response can be one of the most robust signatures of Nrf2 activation in humans, yet less attention is placed on the regulation of these genes and its consequences.…”

Section: The Keap1/nrf2 Systemmentioning

confidence: 99%

“…Knockdown of Nrf2 in HepG2 cells led to a reduction of AKR7A3 mRNA and AKR7A3 protein and increased sensitivity to acetaminophen-induced cytotoxicity. 47 Analysis of the human AKR gene promoters identified the existence of multiple AREs in 13/15 human genes, and many have subsequently been found to be functional, Table 2. 46 …”

Section: Evidence That Human Akr Genes Are Regulated By Aresmentioning

confidence: 99%

Aldo-Keto Reductase Regulation by the Nrf2 System: Implications for Stress Response, Chemotherapy Drug Resistance, and Carcinogenesis

Penning

2016

Chem. Res. Toxicol.

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Human aldo-keto reductases (AKRs) are NAD(P)H-dependent oxidoreductases that convert aldehydes and ketones to primary and secondary alcohols for subsequent conjugation reactions and can be referred to as “phase 1” enzymes. Among all the human genes regulated by the Keap1/Nrf2 pathway, they are consistently the most overexpressed in response to Nrf2 activators. Although these enzymes play clear cytoprotective roles and deal effectively with carbonyl stress, their upregulation by the Keap1/Nrf2 pathway also has a potential dark-side, which can lead to chemotherapeutic drug resistance and the metabolic activation of lung carcinogens (e.g., polycyclic aromatic hydrocarbons). They also play determinant roles in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone metabolism to R- and S-4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol. The overexpression of AKR genes as components of the “smoking gene” battery raises the issue as to whether this is part of a smoking stress response or acquired susceptibility to lung cancer. Human AKR genes also regulate retinoid, prostaglandin, and steroid hormone metabolism and can regulate the local concentrations of ligands available for nuclear receptors (NRs). The prospect exists that signaling through the Keap1/Nrf2 system can also effect NR signaling, but this has remained largely unexplored. We present the case that chemoprevention through the Keap1/Nrf2 system may be context dependent and that the Nrf2 “dose-response curve” for electrophilic and redox balance may not be monotonic.

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“…Although much APAP is metabolized via conjugation with glucuronic acid and sulfate and then excreted, a portion of APAP is converted by cytochrome P-450 metabolism to a reactive quinone form, N-acetyl-p-benzoquinone imine (NAPQI), which is inactivated by conjugation with glutathione (GSH) [4]. Once the pool of GSH is exhausted, any remained N-acetyl-p-benzoquinone imine covalently binds cellular macromolecules induces a series of molecular events that include alkylation of proteins, membrane lipid peroxidation, mitochondrial dysfunction, imbalance of intracellular calcium, formation of reactive oxygen species and reactive nitrogen species [5–6]. APAP-induced hepatocellular damage and necrotic and apoptotic cell death can result in severe centrilobular hepatotoxicity and acute liver failure [7–8].…”

Section: Introductionmentioning

confidence: 99%

Adenosine 5′-monophosphate blocks acetaminophen toxicity by increasing ubiquitination-mediated ASK1 degradation

et al. 2016

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Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the world. Hepatic c-jun NH2-terminal protein kinase (JNK) activation is thought to be a consequence of oxidative stress produced during APAP metabolism. Activation of JNK signals causes hepatocellular damage with necrotic and apoptotic cell death. Here we found that APAP caused a feedback increase in plasma adenosine 5′-monophsphate (5′-AMP). We demonstrated that co-administration of APAP and 5′-AMP significantly ameliorated APAP-induced hepatotoxicity in mice, without influences on APAP metabolism and its analgesic function. The mechanism of protection by 5′-AMP was through inhibiting APAP-induced activation of JNK, and attenuating downstream c-jun and c-fos gene expression. This was triggered by attenuating apoptosis signal-regulated kinase 1(ASK1) methylation and increasing ubiquitination-mediated ASK1 protein degradation. Our findings indicate that replacing the current APAP with a safe and functional APAP/5′-AMP formulation could prevent APAP-induced hepatotoxicity.

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Aldo-keto reductase-7A protects liver cells and tissues from acetaminophen-induced oxidative stress and hepatotoxicity

Cited by 48 publications

References 49 publications

Overexpression of Aldose Reductase Render Mouse Hepatocytes More Sensitive to Acetaminophen Induced Oxidative Stress and Cell Death

Overexpression of Aldose Reductase Render Mouse Hepatocytes More Sensitive to Acetaminophen Induced Oxidative Stress and Cell Death

Aldo-Keto Reductase Regulation by the Nrf2 System: Implications for Stress Response, Chemotherapy Drug Resistance, and Carcinogenesis

Adenosine 5′-monophosphate blocks acetaminophen toxicity by increasing ubiquitination-mediated ASK1 degradation

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