Protection against Acetaminophen Toxicity in CYP1A2 and CYP2E1 Double-Null Mice

Zaher, Hani; Buters, Jeroen; Ward, Jerrold M.; Bruno, Mary K.; Lucas, Angela M.; Stern, Stęphan T.; Cohen, Steven D.; Gonzalez, Frank J.

doi:10.1006/taap.1998.8501

Cited by 292 publications

(206 citation statements)

References 31 publications

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“…Indeed, in agreement with this observation, mice lacking expression of CYP1A2 and CYP2E1 are resistant to acetaminophen-induced hepatotoxicity. 12 The lack of expression of Glu1 was consistent with earlier studies where Glu1 was identified as a potential target gene of ␤-catenin by transgenic over-expression of ␤-catenin in mice. 13 Activation of the Wnt pathway by coculturing epithelial cells with fetal hepatocytes and adenovirus-forced expression of ␤-catenin also implicated ␤-catenin in control of the Glu1.…”

supporting

confidence: 90%

Role of β-catenin in the adult liver

Gonzalez

2006

Hepatology

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supporting

confidence: 90%

Role of β-catenin in the adult liver

Gonzalez

2006

Hepatology

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“…38,39 Mice lacking both CYP1A2 and CYP2E1 have been shown to be almost completely resistant to acetaminophen challenge. 40 As expected by the loss of CYP1A2 and CYP2E1 expression, Alb-Cre;␤-catenin loxP/loxP mice are resistant to acetaminophen toxicity. In contrast to the prominent hepatocyte necrosis observed in control mice, Alb-Cre;␤-catenin loxP/loxP mice do not show histologically detectable signs of liver injury.…”

Section: Discussionmentioning

confidence: 92%

Liver-specific loss of β-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice

et al. 2006

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There is accumulating evidence that Wnt/␤-catenin signaling is involved in the regulation of liver development and physiology. The presence of genetic alterations resulting in constitutive ␤-catenin stabilization in human and murine liver tumors also implicates this pathway in hepatocyte proliferation. In the present study, we generated hepatocyte-specific ␤-catenin knockout mice to explore the role of ␤-catenin in liver function. Conditional knockout mice were born at the expected Mendelian ratio and developed normally to adulthood, indicating ␤-catenin is dispensable for essential liver function under normal breeding conditions. However, the liver mass of knockout mice was 20% less than those of mice in the control groups. Expression analysis revealed loss of genes required for glutamine synthesis in knockout mice. Loss of the liver glutamine synthesis pathway did not affect the blood ammonia level in mice fed a standard diet, yet, knockout mice showed significantly elevated blood ammonia levels with high-protein dietary feeding. Furthermore, the expression of two cytochrome P450 enzymes, CYP1A2 and CYP2E1, was almost completely abolished in livers from hepatocyte-specific ␤-catenin knockout mice. Consequently, these mice were resistant to acetaminophen challenge, confirming the requirement of these cytochrome P450 enzymes for metabolism of xenobiotic substances. ␤ -Catenin is an adapter protein that fulfills two distinct roles in cells. As a part of an adherens junction complex, it interacts with transmembrane proteins of the cadherin family to promote cell-cell adhesion. In addition, ␤-catenin is an integral part of the canonical Wnt signaling pathway known to regulate cell proliferation, differentiation, and stem cell maintenance in a wide variety of tissues. 1-3 Wnt ligands are secreted proteins that bind to cognate frizzled receptors expressed in the cell membrane of Wnt-responsive cells. In the absence of Wnt signals, cytoplasmic ␤-catenin is phosphorylated by glycogen synthase kinase 3␤, a modification that triggers rapid proteosomal degradation of ␤-catenin. Upon stimulation with Wnt ligands, cytoplasmic ␤-catenin is stabilized and translocates to the nucleus, where it forms active transcription complexes with members of the TCF/LEF1 transcription factor family.There is accumulating evidence that indicates a role for Wnt/␤-catenin signaling in hepatocyte proliferation. Micsenyi et al. reported nuclear/cytoplasmic localization of ␤-catenin in hepatocytes during early developmental stages, which gradually decrease with progression of organ development. During liver development, the level of nuclear/cytoplasmic ␤-catenin expression correlates well with the proliferative activity of hepatocytes. 4 Suppression of ␤-catenin by antisense oligonucleotides in ex vivo liver cultures results in decreased cell proliferation and increased apoptosis of hepatocytes. 5 Conversely, transgenic expression of N-terminally truncated ␤-catenin results in increased hepatocyte proliferation and hepatomegaly, 6 a finding that ...

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“…CYP2E1 knockout mice were highly resistant to liver toxicity as compared to wild type mice treated with acetaminophen (49). Mice lacking both CYP2E1 and 1A2 were almost completely resistant to acetaminophen toxicity (189). The combination of ethanol plus isopentanol caused an increase in acetaminophen hepatotoxicity in CYP2E1 knockout mice which was sensitive to the CYP3A inhibitor, triacetyloleandomycin, leading to the suggestion that both CYP2E1 and CYP3A contribute to acetaminophen toxicity in ethanol plus isopentanol-treated mice (190).…”

Section: The Cyp2e1 Knockout Mousementioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

651

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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Protection against Acetaminophen Toxicity in CYP1A2 and CYP2E1 Double-Null Mice

Cited by 292 publications

References 31 publications

Role of β-catenin in the adult liver

Role of β-catenin in the adult liver

Liver-specific loss of β-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice

CYP2E1 and oxidative liver injury by alcohol

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