Role of CYP3A in Ethanol-Mediated Increases in Acetaminophen Hepatotoxicity

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

doi:10.1006/taap.1996.8081

Cited by 53 publications

(39 citation statements)

References 36 publications

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“…Inhibition of Cyp3A prevented APAP hepatotoxicity (Kostrubsky et al, 1997), whereas caffeine, dexamethazone, troglitazone or pregnenolone 16 alpha-carbonitrile, all of Expression data was normalized by mean value (global normalization; adjusted to an arbitrary value of 500) and filtering of the genes by flags (present or marginal call at least 12 of the 24 samples in each experiment) was performed. The fold change of each of the probe sets by the drug was calculated and the numbers of the genes showing more than 2-fold or less than half of control value were counted for each age.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

et al. 2006

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-In order to verify the influence of the rat age on hepatotoxicity, male Sprague-Dawley rats of 6 (young) and 12 (adult) weeks of age were orally administered acetaminophen (APAP), isoniazid (INH), or carbon tetrachloride (CCl4). Liver samples were obtained in a time-course manner, and changes in gene expression examined by an Affymetrix GeneChip. APAP caused more prominent hepatic injury with respect to pathology and blood biochemistry in adults than in young rats, whereas no obvious agerelated differences were observed in INH-or CCl4-treated rats. Comparing gene expression in control rats, CYP3A13 was higher and GSTY2c was lower in adults, suggesting that production of the active metabolite of APAP is higher and its detoxification is lower in adults. The total amount of glutathione and total SH in rat liver was found to be higher in adult rats whereas the extent of its reduction by APAP was larger in adults. A detailed analysis of genes showing age-related differences revealed that some of them were different not in their extent but in their time course, i.e., the stress responses occurred earlier in the young than in the adult, resulting in a difference at 24 hr after dosing. These results suggest that the age-related difference in toxicity would be attributed to a higher expression of CYP3A13, producing the active metabolite of APAP as well as the lower expression of the detoxification enzyme, GSTY2c, in adult rats. Furthermore, these differences affect the time course of APAP toxicity. The present study clearly depicts the advantage of the multi-time, multi-dose protocol employed in our project for analyzing the mechanism of toxicity by gene expression profiling.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

et al. 2006

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“…For investigations of APAP hepatotoxicity and TAO protection, the liquid diets were replaced with water 11 h before the administration of APAP to allow for the elimination of EIP, because as little as 5 mM ethanol in the bloodstream was shown to be protective against APAP hepatotoxicity (Thummel et al, 1988). TAO (500 mg/kg) was prepared in acid-saline as described previously (Pessayre et al, 1981;Kostrubsky et al, 1997) and administered i.p. 2 h before APAP administration.…”

Section: Methodsmentioning

confidence: 99%

“…2 h before APAP administration. APAP, at the doses specified in the figure legends, was prepared as described previously (Kostrubsky et al, 1997) and administered intragastrically (i.g.) to mimic the route of human ingestion.…”

Section: Methodsmentioning

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: 97%

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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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“…CYP3A is also reported to be involved in the metabolism and hepatotoxicity of AP, 48 because ethanol (given as the DeCarli-Lieber diet) induces CYP3A in addition to CYP2E. 49 Whether or not ethanol given in drinking water induces CYP3A remains to be studied.…”

Section: Discussionmentioning

confidence: 99%

Acarbose Alone or in Combination With Ethanol Potentiates the Hepatotoxicity of Carbon Tetrachloride and Acetaminophen in Rats

et al. 1999

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Acarbose reduces the absorption of monosaccharides derived from dietary carbohydrates, which play an important role in the metabolism and toxicity of some chemical compounds. We studied the effects of acarbose on the hepatotoxicity of carbon tetrachloride (CCl 4 ) and acetaminophen (AP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 2E1 (CYP2E1). Male Sprague-Dawley rats were kept on a daily ration (

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Role of CYP3A in Ethanol-Mediated Increases in Acetaminophen Hepatotoxicity

Cited by 53 publications

References 36 publications

Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

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

Acarbose Alone or in Combination With Ethanol Potentiates the Hepatotoxicity of Carbon Tetrachloride and Acetaminophen in Rats

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