Plasma-Paracetamol Half-Life and Hepatic Necrosis in Patients With Paracetamol Overdosage

Prescott, L. F.; Roscoe, P.; Wright, N.; Brown, S. S.

doi:10.1016/s0140-6736(71)91125-1

Cited by 590 publications

(187 citation statements)

References 10 publications

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“…However, overdose can cause fatal centrilobular hepatic necrosis. 36,37 Cytochrome P450 enzymes transform acetaminophen into a reactive metabolite that covalently binds critical cellular proteins. These interactions impair cellular function and consequently lead to cell death.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…The non-steroidal analgesic-antipyretic drug, acetaminophen, is one of the safest over-thecounter drugs when used in recommended doses, but is capable of producing massive hepatic necrosis on acute overdose or chronic low dose use (Prescott et al, 1971;Wilkinson et al, 1977;Bonkovsky et al, 1994). However, different treatment strategies have been proposed to ameliorate or prevent acetaminophen-induced hepatotoxicity (Mitchell et al, 1974;Bessems and Vermeulen, 2001).…”

Section: Discussionmentioning

confidence: 99%

Protective effect of oral ascorbic acid (vitamin c) against acetaminophen- induced hepatic injury in rats

Adeneye¹,

Olagunju²

2010

African Journal of Biomedical Research

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The incidence of acetaminophen-induced hepatotoxicity is reported to be on the increase, with limited therapeutic or chemoprophylactic options. In the present in vivo study, single daily oral doses (100 -500 mg/kg) of ascorbic acid (ASC) were investigated for their protective effects against acetaminophen (APAP)-induced hepatotoxicity in 4 groups of rats made up of 6 rats per group for 14 days. Also, effects of the doses on body weights taken on the 1 st , 7 th and 15 th day of the experiment were also investigated. On the 15 th day, blood samples for serum ALT, AST and FBG assay were collected through cardiac puncture under inhaled diethyl ether anaesthesia. Rat livers were also studied for histopathology. Results showed that treatment with APAP intraperitoneal injection induced significant (P<0.001) elevation in the serum levels of ALT and AST while inducing significant (P<0.05) decrease in the serum FBG. The hepatotoxicity was also corroborated by the histopathological lesion of lipid peroxidation characterized by diffuse ballooning degeneration with lymphocytic infiltration. Significant (P<0.01) weight loss and hypoglycaemia were also associated with APAP-induced hepatotoxicity. However, these alterations were attenuated in ASC pretreated rats dose dependently. Also, APAP-induced hypoglycaemia and weight loss were significantly (P<0.01, P<0.001) enhanced by ASC in dose related pattern. Thus, results of this study showed that 100 -500 mg/kg/day was protective against APAP-induced hepatotoxicity, effect which could have been mediated via its inherent free radical scavenging and/or free radicals generation inhibiting activities.

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“…A fatal outcome is likely if the half-life exceeds 10-12 h (Prescott, Wright, Roscoe & Brown, 1971;. The metabolism of other drugs is also impaired and combined overdosage of paracetamol with central nervous system depressants is particularly dangerous since coma may be prolonged for many days (Forrest, Roscoe, Prescott & Stevenson, 1974).…”

Section: Paracetamolpoisoning and Acute Hepatic Necrosismentioning

confidence: 99%

The third Lilly Prize Lecture. University of London, January, 1979. The nephrotoxicity and hepatotoxicity of antipyretic analgesics.

Prescott¹

1979

Brit J Clinical Pharma

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Plasma-Paracetamol Half-Life and Hepatic Necrosis in Patients With Paracetamol Overdosage

Cited by 590 publications

References 10 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

Protective effect of oral ascorbic acid (vitamin c) against acetaminophen- induced hepatic injury in rats

The third Lilly Prize Lecture. University of London, January, 1979. The nephrotoxicity and hepatotoxicity of antipyretic analgesics.

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