Additive effects of inducers and fasting on acetaminophen hepatotoxicity

Pessayre, Dominique; Wandscheer, Joao-Carlos; Cobert, Barton; Level, Regine; Degott, Claude; Batt, Anne Marie; Martin, Nicole; Benhamou, Jean Pierre

doi:10.1016/0006-2952(80)90201-4

Cited by 60 publications

(14 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…APAP-induced hepatotoxicity was observed at a single oral dose of 1000 mg/kg with fasting but was not observed without fasting (data not shown). Previous reports demonstrated that fasting caused a GSH decrease in liver (33,34). Moreover, transcription of the CYP2E1 gene is potently activated by fasting (35).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Akai

Hosomi

Minami

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Drug-induced hepatotoxicity is mainly caused by hepatic glutathione (GSH) depletion. In general, the activity of rodent glutathione S-transferase is 10 to 20 times higher than that of humans, which could make the prediction of drug-induced hepatotoxicity in human more difficult. ␥-Glutamylcysteine synthetase (␥-GCS) mainly regulates de novo synthesis of GSH in mammalian cells and plays a central role in the antioxidant capacity of cells. In this study, we constructed a GSH-depletion experimental rat model for the prediction of human hepatotoxicity. An adenovirus vector with short hairpin RNA against rat ␥-GCS heavy chain subunit (GCSh) (AdGCSh-shRNA) was constructed and used to knock down the GCSh. In in vitro study in H4IIE cells, a rat hepatoma cell line, GCSh mRNA and protein were significantly decreased by 80% and GSH was significantly decreased by 50% 3 days after AdGCSh-shRNA infection. In the in vivo study in rat, the hepatic GSH level was decreased by 80% 14 days after a single dose of AdGCSh-shRNA (2 ؋ 10 11 pfu/ml/ body), and this depletion continued for at least 2 weeks. Using this GSH knockdown rat model, acetaminophen-induced hepatotoxicity was shown to be significantly potentiated compared with normal rats. This is the first report of a GSH knockdown rat model, which could be useful for highly sensitive tests of acute and subacute toxicity for drug candidates in preclinical drug development.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In previous APAP-induced hepatotoxicity studies, the rats were generally fasted for half or 1 day before drug administration (31)(32)(33). In the present study, in order to clarify the involvement of GSH depletion, the rats were not fasted before treatment.…”

Section: Discussionmentioning

confidence: 99%

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Akai

Hosomi

Minami

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The GSH concentration is normally maintained at a high level to ensure cell survival by an active process of resynthesis (Tate and Meister, 1974;Kosower and Kosower, 1978). Previous experimental studies have shown that diethylmaleate (Mitchell et ai, 1973), prolonged fasting (Pessayre et al, 1980) and protein malnutrition (Leaf and Neuberger, 1947) decrease hepatic GSH content and so may potentiate hepatic injury by reactive metabolites.…”

Section: Introductionmentioning

confidence: 99%

Effect of Haemorrhage on Hepatic Glutathione Concentration: An Experimental Study in the Pig

Shi

Rose

Ham

1986

Aust J Exp Biol Med

View full text Add to dashboard Cite

Summary. Depletion in the hepatic concentration of reduced glutathione (GSH) may potentiate liver injury resulting from toxic metabolites. Patients who have had severe haemorrhage frequently develop hepatic dysfunction and we have shown that the hepatic GSH level is decreased in these patients. The present study has examined the time-course effect of a 30% haemorrhage on the hepatic GSH level by sequential biopsies of the liver. Acute and chronic experiments were performed and, in both, the hepatic concentration of GSH fell during the first 6 h after haemorrhage; this fall was followed by a significant rebound elevation at 24 h. In the chronic haemorrhage experiment the hepatic GSH level was normal at 1 week after haemorrhage. Thus, the susceptibility of the liver to toxic metabolite injury after haemorrhage persists for less than 24 h in this experimental model and haemorrhage appears to have no long term effect on the hepatic GSH concentration.

show abstract

“…Many investigators have reported that di etary modifications can affect hepatic gluta thione levels [Maruyama et al, 1968;McLean and Day, 1975;Pessayre et al, 1979Pessayre et al, , 1980Lautcrberg and Mitchell, 1981], This modification can be responsible for changes in the toxicity o f certain hepatotoxins, especially those compounds which arc detoxified by glutathione [McLean and Day, 1975;Pessayre et al, 1979Pessayre et al, , 1980Lautcrberg and Mitchell, 1981]. Other studies have shown that feeding schedules can synchro nize a variety o f circadian rhythms such as a rhythm in ethanol clearance [Sturtevanl andGarber, 1980, 1981], An experiment was conducted to examine the relationship between food consumption schedules and hepatic glutathione content.…”

Section: Circadian Rhythms In Food Consumption and Hepatic Glutathionmentioning

confidence: 99%

“…1975;Wendel et al, 1979;Pessayre et al, 1979Pessayre et al, , 1980, In this experiment, mice were fasted for 12 h prior to the administration of acetaminophen or measurement o f hepatic glutathione levels. The results arc shown in figure 6.…”

Section: Effect O F Fasting On Circadian Rhythms In Acetaminophen Letmentioning

confidence: 99%

Factors Influencing Circadian Rhythms in Acetaminophen Lethality

et al. 1984

View full text Add to dashboard Cite

Experiments were conducted to examine the effects of changes in lighting schedules and food consumption on circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice. Under a normal lighting schedule (light: 06.00–18.00 h), male mice exhibited a circadian rhythm in acetaminophen lethality (peak: 18.00 h; nadir: 06.00, 10.00 h) and an inverse rhythm in hepatic glutathione concentrations (peak: 06.00, 10.00 h; nadir: 18.00 h). Under a reversed lighting schedule (light: 18.00–06.00 h) the glutathione rhythm was reversed and the rhythm in acetaminophen lethality was altered showing greater sensitivity to the drug. Under continuous light, there was a shift in the acetaminophen lethality and the hepatic glutathione rhythms. Under continuous dark, both rhythms were abolished. Under a normal lighting regimen, hepatic glutathione levels were closely correlated with food consumption; i.e., both were increased during the dark phase and decreased during the light phase. Fasting the mice for 12 h abolished the rhythms in acetaminophen lethality and hepatic glutathione levels; moreover, the lethality was increased and the hepatic glutathione levels were decreased. These experiments show that both lighting schedules and feeding can alter the circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice.

show abstract

Additive effects of inducers and fasting on acetaminophen hepatotoxicity

Cited by 60 publications

References 13 publications

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Effect of Haemorrhage on Hepatic Glutathione Concentration: An Experimental Study in the Pig

Factors Influencing Circadian Rhythms in Acetaminophen Lethality

Contact Info

Product

Resources

About