Acetaminophen hepatotoxicity precipitated by short-term treatment of rats with ethanol and isopentanol

Sinclair, Jacqueline F.; Szakacs, Juliana G.; Wood, Sheryl G.; Kostrubsky, Vsevolod E.; Jeffery, Elizabeth H.; Wrighton, Steven; Bement, William J.; Wright, D L; Sinclair, Peter R.

doi:10.1016/s0006-2952(99)00349-4

Cited by 36 publications

(51 citation statements)

References 44 publications

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“…Alcohol has been shown to induce CYP3A along with CYP2E1 in rats (Louis et al, 1994;Roberts et al, 1995) and in primary cultures of human and rat hepatocytes (Sinclair et al, 1991;Kostrubsky et al, 1995a). TAO, an inhibitor of CYP3A, protected rats from alcohol-mediated increases in APAP hepatotoxicity, suggesting a role of CYP3A (Kostrubsky et al, 1997;Sinclair et al, 2000b). Here, we compared EIP-treated wild-type and Cyp2e1(Ϫ/Ϫ) mice to ascertain the roles of CYP2E1 and CYP3A in alcohol-mediated increases in APAP hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Cytosolic fractions were extracted with an equal volume of 10% (w/v) trichloroacetic acid (TCA), whereas 5% (w/v) TCA was added directly to the mitochondrial pellets. The resulting TCA extracts were centrifuged at 10,000g for 10 min at 4°C, and the supernatants were used to analyze GSH as described previously (Sinclair et al, 2000b). The TCAextracted pellets were solubilized in 0.1 N NaOH/0.1% (w/v) SDS for protein determinations.…”

Section: Methodsmentioning

confidence: 99%

“…was administered at 9 h after withdrawal from the diet. At 2 h after TAO administration, the animals were euthanized, and hepatic microsomes were prepared and analyzed for MROD activity, PNPH activity, and triazolam 4-hydroxylation activity ( In all studies on alcohol-mediated APAP hepatotoxicity in experimental animals, alcohol is withdrawn 11 to 24 h before APAP administration (for review, see Sinclair et al, 2000b). During this withdrawal period, alcohol-induced levels of CYP2E1 decreased to constitutive levels in mice (Fig.…”

Section: Effect Of Tao On Alcohol-mediated Increases In Apap Hepatotomentioning

confidence: 99%

“…(300 mg/kg to wild-type mice and 600 mg/kg to Cyp2e1(Ϫ/Ϫ) mice). Mitochondrial (A) and cytosolic (B) fractions were prepared from freshly harvested liver, as described under Materials and Methods, and GSH was measured, as described previously (Sinclair et al, 2000b Cyp2e1(Ϫ/Ϫ) mice (Wolf et al, 2004). Here we found that, at the time of APAP administration, CYP3A-catalyzed activity, measured as the 6␤-hydroxylation of testosterone, was also greater in wild-type mice compared with Cyp2e1(Ϫ/Ϫ) mice, all pretreated with EIP.…”

Section: Figmentioning

confidence: 99%

“…The combined alcohol treatment resulted in no further increase in CYP2E1 than that caused by either alcohol alone, suggesting that CYP3A is responsible for the synergistic increase in APAP hepatotoxicity (Kostrubsky et al, 1995b). In another study, triacetyloleandomycin (TAO), an inhibitor of CYP3A (Pessayre et al, 1981;Newton et al, 1995), protected rats pretreated with ethanol, either alone or in combination with isopentanol, from alcohol-mediated increases in APAP hepatotoxicity, also supporting a role of CYP3A (Kostrubsky et al, 1997;Sinclair et al, 2000b).…”

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confidence: 96%

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Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Wolf¹,

Wood²,

Allard³

et al. 2007

Drug Metab Dispos

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ABSTRACT:CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(؊/؊) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(؊/؊) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(؊/؊) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(؊/؊) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(؊/؊) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.Acetaminophen (APAP) is considered to be a relatively safe drug and is widely prescribed and used for its analgesic and antipyretic properties. The first reports of hepatotoxicity in humans resulting from APAP overdose were in 1966 ( Thomson and Prescott, 1966). Today, APAP is a frequent cause of liver failure and the leading cause of death due to accidental and deliberate overdose (for review, see Bromer and Black, 2003). APAP is mainly glucuronidated and sulfated in the liver by phase II metabolic pathways, leading to excretion of the drug. However, APAP is also metabolized by certain forms of cytochromes P450 (P450s) to N-acetyl-p-benzoquinone imine (NAPQI), a highly electrophilic metabolite that is considered to be responsible for triggering the ensuing liver damage. CYP1A2, CYP2E1, and CYP3A are three forms of rat and human P450s active in the conversion of APAP to NAPQI, with CYP2E1 and CYP3A having greater intrinsic activity than CYP1A2 (Patten et al., 1993;Thummel et al., 1993). Reduced glutathione (GSH) reacts with NAPQI, resulting in the inactivation of this reactive metabolite. When GSH levels become depleted, liver damage can occur as a result of the

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Effect Of Tao On Alcohol-mediated Increases In Apap Hepatotomentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 96%

See 3 more Smart Citations

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Wolf¹,

Wood²,

Allard³

et al. 2007

Drug Metab Dispos

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Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous DA‐8159, a new erectogenic, in rats

Kim¹,

Shim²,

Lee³

et al. 2005

Biopharm & Drug Disp

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In order to find what types of hepatic microsomal cytochrome P450 (CYP) isozymes are involved in the metabolism of DA-8159 and in the formation of DA-8164 in rats, enzyme inducers, such as dexamethasone, phenobarbital, 3-methylcholanthrene and isoniazid, and enzyme inhibitors, such as troleandomycin and quinine, were pretreated in rats. After a 1 min intravenous administration of DA-8159 at a dose of 30 mg/kg to rats pretreated with dexamethasone (a main inducer of CYP3A1/2 in rats), the total areas under the plasma concentration-time curve from time zero to time infinity (AUC) values of DA-8159 (283 versus 349 microg min/ml) and DA-8164 (98.0 versus 79.8 microg min/ml) were significantly smaller and greater, respectively, than those in control rats. However, the AUC values of DA-8159 were not significantly different after pretreatment with phenobarbital, isoniazid and 3-methylcholanthrene (main inducers of CYP2B1/2, 2E1 and 1A1/2, respectively, in rats). In rats pretreated with troleandomycin (a main inhibitor of CYP3A1/2 in rats), the AUC values of DA-8159 (435 versus 370 microg min/ml) and DA-8164 (34.8 versus 76.5 microg min/ml) were significantly greater and smaller, respectively. However, in rats pretreated with quinine (a main inhibitor of CYP2D1 in rats), the AUC of DA-8159 was comparable to that in control rats. The above data indicate that DA-8159 was metabolized and DA-8164 was formed mainly via CYP3A1/2 in rats.

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Negligible pharmacokinetic interaction between oral DA-8159, a new erectogenic, and amlodipine in rats

Lee

Kim

Kwon

et al. 2006

Biopharm. Drug Dispos.

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A pharmacokinetic interaction between oral DA-8159 and amlodipine was evaluated in male Sprague-Dawley rats. In rats pretreated with troleandomycin (a main inhibitor of CYP3A1/2 in rats), the AUC(0-6 h) of amlodipine was significantly greater than the controls (34.5+/-6.01 compared with 28.0+/-4.70 microg min/ml), indicating that amlodipine is metabolized via CYP3A1/2 in rats. It was reported that the metabolism of DA-8159 and the formation of DA-8164 (a metabolite of DA-8159) were mainly mediated via CYP3A1/2 in rats, and amlodipine significantly inhibited the CYP3A2 in rats. Therefore, a pharmacokinetic interaction between the two drugs could be expected. However, after oral administration of DA-8159 at a dose of 30 mg/kg with or without oral amlodipine at a dose of 5 mg/kg to rats, the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between the two groups of rats. Similar results were also obtained from amlodipine between with and without DA-8159. The above data indicated that the pharmacokinetic interaction between oral DA-8159 and amlodipine was almost negligible in rats.

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Acetaminophen hepatotoxicity precipitated by short-term treatment of rats with ethanol and isopentanol

Cited by 36 publications

References 44 publications

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Role of CYP3A and CYP2E1 in Alcohol-Mediated Increases in Acetaminophen Hepatotoxicity: Comparison of Wild-Type andCyp2e1(–/–) Mice

Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous DA‐8159, a new erectogenic, in rats

Negligible pharmacokinetic interaction between oral DA-8159, a new erectogenic, and amlodipine in rats

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