Selective protein arylation and the age dependency of acetaminophen hepatotoxicity in mice

Beierschmitt, William P.; Brady, Joseph T.; Bartolone, John B.; Wyand, D. S.; Khairallah, Edward A.; Cohen, Steven D.

doi:10.1016/0041-008x(89)90180-4

Cited by 50 publications

(18 citation statements)

References 29 publications

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“…(10) found less necrosis in 3-and 8-d-old mice compared with 3S-d-old mice. Beierschmitt et al (21) found that 3-mo-old mice were more susceptible to paracetamol hepatotoxicity than 1-and 2-mo-old mice.…”

Section: Discussionmentioning

confidence: 99%

Postnatal Mice Have Low Susceptibility to Paracetamol Toxicity

1991

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ABSTRACT. The hepatotoxicity of paracetamol in mice of 2, 3, 8-10, 24-26, 32-34, and 52-54 wk of age was determined by lethality data, histopathologic examination of the liver, and appearance of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase activities in the plasma over an 8-h exposure period. At a dose of 300 mg/kg, there was evidence of hepatocytic necrosis and transaminase leakage in the 32-to 34-and 52-to 54-wk-old mice, but lethality was only recorded in the oldest age group. At 500 mg/kg, paracetamol produced 30% lethality in 3-wk-old mice and between 50 and 90% lethality in the adult age groups. There was histologic evidence of hepatocytic necrosis at all of these ages and its extent increased with age. Similarly, there were increases in plasma transaminases in each of these age groups. However, in 2-wk-old mice there was no lethality, no hepatocytic necrosis, and no increase in plasma transaminases. The lack of susceptibility of 2-wk-old mice to paracetamol toxicity was not due to immaturity of the cytochrome P-450 enzymes responsible for metabolism of paracetamol to its reactive metabolite (N-acetyl-p-benzoquinone imine). In fact, the activity of this enzyme pathway in 2-wk-old mice was greater than that in adults. The partial clearance of the glutathione-derived metabolites of paracetamol after a nontoxic (50 mg/kg) dose was 80% greater in 2-wk-old mice than in 8-to 10-wk-old mice. Therefore, despite having greater capacity to generate N-acetyl-p-benzoquinone imine, 2-wk-old mice had no hepatotoxic effects from a dose that killed at least 50% of adult mice. Factors that relate to the detoxification of N-acetyl-p-benzoquinone imine in the liver are implicated in the lesser susceptibility of postnatal mice to paracetamol toxicity. (Pediatr Res 29: 496-499,1991) to detoxify this metabolite by conjugation to GSH (2-4), and a number of incompletely understood processes initiated by NAPQI that lead to cell death (5).It is generally accepted that children are less susceptible to paracetamol toxicity than are adults (6). This impression has developed from clinical observations that the incidence of overdose toxicity is less in the young (7). However, the scientific basis for this has yet to be confirmed.Our present study is aimed at examining developmental aspects of the susceptibility of mice to paracetamol toxicity. Previous work in this field has been conflicting, with some research indicating that young mice (8) and rats (9) are more susceptible to high doses of paracetamol. However, the majority of findings indicate that during the postnatal period young rats and mice are less susceptible to toxicity (10, II). These latter observations have been attributed to the immaturity of the cytochrome P-450-linked mixed function oxidase enzymes in the postnatal period and the consequent decrease in the rate of activation of paracetamol to NAPQI (10) or to a lack of susceptibility to hepatotoxins in general (12). We have recently observed that hepatocytes from postnatal mice are less su...

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Section: Discussionmentioning

confidence: 99%

Postnatal Mice Have Low Susceptibility to Paracetamol Toxicity

1991

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“…NAPQI depletes glutathione in hepatocytes and covalently binds to intracellular proteins resulting in mitochondrial dysfunction and oxidant-induced stress (Masubuchi et al, 2005). There are significant strain-specific differences in the susceptibility of mice and rats to APAP-induced injury (Tarloff et al, 1989;Mehendale, 2005), and susceptibility to injury can increase with advancing age (Beierschmitt et al, 1986(Beierschmitt et al, , 1989Tarloff et al, 1991Tarloff et al, , 1996.…”

Section: Introductionmentioning

confidence: 99%

Stress resistance and aging: Influence of genes and nutrition

Harper

Salmon

Chang

et al. 2006

Mechanisms of Ageing and Development

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Previous studies have shown that dermal fibroblast cell lines derived from young adult mice of the long-lived Snell dwarf (dw/dw), Ames dwarf (df/df) and growth hormone receptor knockout (GHR-KO) mouse stocks are resistant, in vitro, to the cytotoxic effects of hydrogen peroxide, cadmium, ultraviolet light, paraquat, and heat. Here we show that, in contrast, fibroblasts from mice on low-calorie (CR) or low methionine (Meth-R) diets are not stress resistant in culture, despite the longevity induced by both dietary regimes. A second approach, involving induction of liver cell death in live animals using acetaminophen (APAP), documented hepatotoxin resistance in the CR and Meth-R mice, but dw/dw and GHR-KO mutant mice were not resistant to this agent, and were in fact more susceptible than littermate controls to the toxic effects of APAP. These data thus suggest that while resistance to stress is a common characteristic of experimental life span extension in mice, the cell types showing resistance may differ among the various models of delayed or decelerated aging.

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“…While earlier work characterized this binding radiometrically, subsequent investigations conducted with acetaminophen using antibody technology [22] revealed that covalent binding is not random throughout the cell, but is highly specific to a rather limited number of specific proteins in different cellular fractions. This and previous investigations [23] suggest that binding to a single or number of different proteins may ultimately elicit the toxic response. The observation that hepatotoxicity is strongly correlated with covalent binding to specific cellular proteins has been established for bromobenzene [24][25] and APAP [26].…”

Section: Characteristics and Pathogenesis Of Adr/bmentioning

confidence: 85%

Reactive Intermediates and the Pathogenesis of Adverse Drug Reactions: The Toxicology Perspective

Amacher¹

2006

CDM

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Severe adverse drug responses are infrequent but occasionally serious events that are not readily predictable at the preclinical development level using only non-human or in vitro models. A common characteristic of the more serious toxicities is generation of short-lived and highly reactive electrophilic species in some individuals. The objective here is to review the literature for toxicological mechanisms that underlie known adverse drug reactions and then categorize the biological consequences of reactive chemical intermediates and radicals in terms of human risk factors and known metabolic variables. Xenobiotics described as being associated with rare but potentially serious adverse events affecting liver, skin, or causing blood dyscrasias tend to have three of four essential characteristics, (1) they are capable of forming short-lived reactive intermediates (RI) or free radicals in target tissues under ideal conditions that are distinct from primary metabolic products, (2) these RI escape/overwhelm the detoxification mechanisms associated with the site of origin or form toxic conjugates, (3) the unconjugated RI must either selectively damage critical proteins or other key macromolecules or (4) the RI acts as a hapten and stimulates an immunological (hypersensitivity) response or overcomes tolerance. Some risk factors may increase the probability of susceptibility, but this remains an active area of research. Because of the complexity of the pathogenesis of some injuries and the role of individual factors, no highly predictive in vitro screening methods are available; however, several methods are evolving that may be used to reveal mechanisms of action when a serious adverse effect is encountered.

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Selective protein arylation and the age dependency of acetaminophen hepatotoxicity in mice

Cited by 50 publications

References 29 publications

Postnatal Mice Have Low Susceptibility to Paracetamol Toxicity

Postnatal Mice Have Low Susceptibility to Paracetamol Toxicity

Stress resistance and aging: Influence of genes and nutrition

Reactive Intermediates and the Pathogenesis of Adverse Drug Reactions: The Toxicology Perspective

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