Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2

Raucy, Judy L.; Lasker, Jerome M.; Lieber, Charles S.; Black, Martin M.

doi:10.1016/0003-9861(89)90278-6

Cited by 450 publications

(236 citation statements)

References 33 publications

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“…30,31 Cytochrome P450-mediated modification of acetaminophen results in formation of highly reactive metabolites that cause liver cell necrosis. To examine the functional significance of the loss of CYP1A2 and CYP2E1, we challenged Alb-Cre;␤-catenin loxP/loxP and control mice with acetaminophen.…”

Section: Resultsmentioning

confidence: 99%

“…30,31 Acetaminophen is one of the most widely used analgesic and antipyretic drugs. However, overdose can cause fatal centrilobular hepatic necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…These interactions impair cellular function and consequently lead to cell death. 30,31 Although both CYP2E1 and CYP1A2 are involved in acetaminophen toxicity, their contributions differ, with CYP2E1 being the enzyme predominantly involved in this process. 30 Studies of CYP1A2-and CYP2E1-null mice have elucidated the roles of both enzymes in acetaminophen toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…30,31 Although both CYP2E1 and CYP1A2 are involved in acetaminophen toxicity, their contributions differ, with CYP2E1 being the enzyme predominantly involved in this process. 30 Studies of CYP1A2-and CYP2E1-null mice have elucidated the roles of both enzymes in acetaminophen toxicity. Whereas CYP1A2-null mice are somewhat protected against high concentrations of acetaminophen, CYP2E1-null mice are highly resistant to acetaminophen toxicity.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…30,31 Acetaminophen is one of the most widely used analgesic and antipyretic drugs. However, overdose can cause fatal centrilobular hepatic necrosis.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2006

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“…This analgesic is also metabolized to a reactive intermediate by CYP2E1. 49 Mice lacking Cyp2e1 were more resistant to acetaminophen-mediated hepatotoxicity when compared to wild-type mice, confirming that CYP2E1 is responsible for mediating toxicity from this drug. These results are in good agreement with in vitro studies, which demonstrate that microsomes from animals treated with ethanol exhibit greater formation of the reactive acetaminophen metabolite.…”

Section: Wwwnaturecom/tpjmentioning

confidence: 89%

Recent advances in P450 research

Raucy

Allen

2001

Pharmacogenomics J

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P450 enzymes comprise a superfamily of heme-containing proteins that catalyze oxidative metabolism of structurally diverse chemicals. Over the past few years, there has been significant progress in P450 research on many fronts and the information gained is currently being applied to both drug development and clinical practice. Recently, a major accomplishment occurred when the structure of a mammalian P450 was determined by crystallography. Results from these studies will have a major impact on understanding structure-activity relationships of P450 enzymes and promote prediction of drug interactions. In addition, new technologies have facilitated the identification of several new P450 alleles. This information will profoundly affect our understanding of the causes attributed to interindividual variations in drug responses and link these differences to efficacy or toxicity of many therapeutic agents. Finally, the recent accomplishments towards constructing P450 null animals have afforded determination of the role of these enzymes in toxicity. Moreover, advances have been made towards the construction of humanized transgenic animals and plants. Overall, the outcome of recent developments in the P450 arena will be safer and more efficient drug therapies.

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Expression and inducibility of P450 enzymes during liver ontogeny

Rich

Boobis

1997

Microsc. Res. Tech.

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Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2

Cited by 450 publications

References 33 publications

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

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

Recent advances in P450 research

Expression and inducibility of P450 enzymes during liver ontogeny

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