Acute hepatotoxicity of acetaminophen in rats treated with ethanol plus isopentanol

Kostrubsky, Vsevolod E.; Wood, Sheryl G.; Bush, Matthew D.; Szakacs, Juliana G.; Bement, William J.; Sinclair, Peter R.; Jeffery, Elizabeth H.; Sinclair, Jacqueline F.

doi:10.1016/0006-2952(95)02155-8

Cited by 32 publications

(17 citation statements)

References 20 publications

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“…A 7-day treatment with ethanol plus isopentanol (EIP) caused essentially no liver damage in either strain of mice, as analyzed histologically (Table 1) and by plasma ALT (results not shown), similar to our previous findings in rats (28,58). However, pretreatment with EIP increased APAP hepatotoxicity compared with APAP alone in HeN mice (Table 1, P Ͻ 0.01) but not in HeJ mice ( Table 1).…”

Section: Apap Hepatotoxicity In Hen Vs Hej Micesupporting

confidence: 89%

“…In experimental studies on alcohol-mediated increases in APAP hepatotoxicity, we and others in the field continue to use the Lieber-DeCarli diet as a way to investigate the effect of chronic alcohol consumption on APAP hepatotoxicity (2,27,28,34,58,63,67,73,74). This diet was developed to overcome the aversion that most strains of rodents have to consume ethanol.…”

Section: Discussionmentioning

confidence: 97%

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Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

Yohe

O’Hara²,

Hunt³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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The objective of this study was to determine whether Toll-like receptor 4 (TLR4) has a role in alcohol-mediated acetaminophen (APAP) hepatotoxicity. TLR4 is involved in the inflammatory response to endotoxin. Others have found that ethanol-mediated liver disease is decreased in C3H/HeJ mice, which have a mutated TLR4 resulting in a decreased response to endotoxin compared with endotoxin-responsive mice. In the present study, short-term (1 wk) pretreatment with ethanol plus isopentanol, the predominant alcohols in alcoholic beverages, caused no histologically observed liver damage in either C3H/HeJ mice or endotoxin-responsive C3H/HeN mice, despite an increase in nitrotyrosine levels in the livers of C3H/HeN mice. In C3H/HeN mice pretreated with the alcohols, subsequent exposure to APAP caused a transient decrease in liver nitrotyrosine formation, possibly due to competitive interaction of peroxynitrite with APAP producing 3-nitroacetaminophen. Treatment with APAP alone resulted in steatosis in addition to congestion and necrosis in both C3H/HeN and C3H/HeJ mice, but the effects were more severe in endotoxin-responsive C3H/HeN mice. In alcohol-pretreated endotoxin-responsive C3H/HeN mice, subsequent exposure to APAP resulted in further increases in liver damage, including severe steatosis, associated with elevated plasma levels of TNF-alpha. In contrast, alcohol pretreatment of C3H/HeJ mice caused little to no increase in APAP hepatotoxicity and no increase in plasma TNF-alpha. Portal blood endotoxin levels were very low and were not detectably elevated by any of the treatments. In conclusion, this study implicates a role of TLR4 in APAP-mediated hepatotoxicity.

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Section: Apap Hepatotoxicity In Hen Vs Hej Micesupporting

confidence: 89%

Section: Discussionmentioning

confidence: 97%

Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

Yohe

O’Hara²,

Hunt³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…These investigators have shown that isopentonol is a potent inducer of CYP3A isoforms in rats and that, in combination with ethanol, it potentiates acetaminophen hepatotoxicity [33], which can be blocked by the CYP3A4 inhibitor triacetyloleandomycin [34]. The presence of induced CYP3A4 activities in chronic alcoholics has also been suggested by findings of increased urinary ratios of 6␤-hydroxycortisol/cortisol in these patients [35].…”

Section: Alcohol and Other Enhancers Of Toxicitymentioning

confidence: 93%

Acetaminophen hepatotoxicity: An update

McClain

Price

Barve

et al. 1999

Curr Gastroenterol Rep

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“…Many isoforms of cytochrome P450 including 1A1, 1A2, 2A1, 2A6, 2B1, 2C11, 2C12, 2E1, 3A1 and 3A4 contribute to the metabolism of paracetamol [95, 97, 169, 171]. More recent studies indicate important roles for CYP1A2 and CYP3A in the metabolism of ethanol and the metabolic activation and hepatotoxicity of paracetamol in animals [87–89, 99, 100, 168, 172]. In man, CYP1A2 does not seem to be quantitatively important in the metabolism of paracetamol to a toxic intermediate [173].…”

Section: Isoenzyme Specificitymentioning

confidence: 99%

Paracetamol, alcohol and the liver

Prescott

2000

Brit J Clinical Pharma

194

106

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It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with`therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol± alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic.The paracetamol±alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol±ethanol interaction is not speci®c for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical.In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the ®rst few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insuf®cient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestioningly accepted this supposed interaction in man for so long with such scant regard for scienti®c objectivity.

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Acute hepatotoxicity of acetaminophen in rats treated with ethanol plus isopentanol

Cited by 32 publications

References 20 publications

Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity

Acetaminophen hepatotoxicity: An update

Paracetamol, alcohol and the liver

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