Effect of Caffeine on Acetaminophen Hepatotoxicity in Cultured Hepatocytes Treated with Ethanol and Isopentanol

DiPetrillo, Keith; Wood, Sheryl G.; Kostrubsky, Vsevolod E.; Chatfield, Kathryn C.; Bement, Jenna; Wrighton, Steven; Jeffery, Elizabeth H.; Sinclair, Peter R.; Sinclair, Jacqueline F.

doi:10.1006/taap.2002.9535

Cited by 20 publications

(6 citation statements)

References 33 publications

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“…In contrast to the findings in rats (Zerilli et al, 1998;Kobayashi et al, 2002;DiPetrillo et al, 2002) and humans (Zerilli et al, 1998), our findings that female-specific and alcohol-induced forms of mouse CYP3A do not contribute appreciably to PNPH activity suggest that minor differences between species in the amino acid sequences of CYP3A are responsible. Differences in substrate specificities of CYP3A have been detected for different forms of CYP3A within the same species.…”

Section: Resultscontrasting

confidence: 56%

“…However, this activity is also catalyzed by expressed forms of human and rat CYP3A (Zerilli et al, 1998;Kobayashi et al, 2002) and rat CYP1A2 (Kobayashi et al, 2002). A role for CYP3A in this reaction was confirmed in intact rats and rat hepatocytes by studies showing that dexamethasone treatment, which induces CYP3A but not CYP2E1 (Sinclair et al, 1991;Zerilli et al, 1998), results in a marked increase in PNPH (Zerilli et al, 1998;DiPetrillo et al, 2002). Dexamethasone-induced PNPH activity is inhibited by troleandomycin, a specific inhibitor of CYP3A (Zerilli et al, 1998;DiPetrillo et al, 2002).…”

mentioning

confidence: 76%

“…A role for CYP3A in this reaction was confirmed in intact rats and rat hepatocytes by studies showing that dexamethasone treatment, which induces CYP3A but not CYP2E1 (Sinclair et al, 1991;Zerilli et al, 1998), results in a marked increase in PNPH (Zerilli et al, 1998;DiPetrillo et al, 2002). Dexamethasone-induced PNPH activity is inhibited by troleandomycin, a specific inhibitor of CYP3A (Zerilli et al, 1998;DiPetrillo et al, 2002). Thus, the findings that rat CYP3A can catalyze PNPH indicate that this reaction cannot be used to specifically measure CYP2E1 enzymatically in rats when CYP3A is also present.…”

mentioning

confidence: 86%

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ROLE OF MOUSE CYP2E1 IN THEO-HYDROXYLATION OFP-NITROPHENOL: COMPARISON OF ACTIVITIES IN HEPATIC MICROSOMES FROMCYP2E1(-/-) AND WILD-TYPE MICE

Wolf

Wood²,

Bement³

et al. 2004

Drug Metab Dispos

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ABSTRACT:Enzymatic activities are routinely used to identify the contribution of individual forms of cytochrome P450 in a particular biotransformation. p-Nitrophenol O-hydroxylation (PNPH) has been widely used as a measure of CYP2E1 catalytic activity. However, rat and human forms of CYP3A have also been shown to catalyze this activity. In mice, the contributions of CYP3A and CYP2E1 to PNPH activity are not known. Here we used hepatic microsomes from Cyp2e1(؊/؊) and wild-type mice to investigate the contributions of constitutively expressed and alcohol-induced murine CYP2E1 and CYP3A to PNPH activity. In liver microsomes from untreated mice, PNPH activity was much greater in wild-type mice compared with Cyp2e1(؊/؊) mice, suggesting a major role for CYP2E1 in catalyzing PNPH activity. Hepatic PNPH activities were not significantly different in microsomes from male and female mice, although the microsomes from females have dramatically higher levels of CYP3A. Treatment with a combination of ethanol and isopentanol resulted in induction of CYP3A proteins in wild-type and Cyp2e1(؊/؊) mice, as well as CYP2E1 protein in wild-type mice. The alcohol treatment increased PNPH activities in hepatic microsomes from wild-type mice but not from Cyp2e1(؊/؊) mice. Our findings suggest that in untreated and alcohol-treated mice, PNPH activity may be used as a specific probe for CYP2E1 and that constitutively expressed and alcohol-induced forms of mouse CYP3A have little to no role in catalyzing PNPH activity.

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Section: Resultscontrasting

confidence: 56%

mentioning

confidence: 76%

mentioning

confidence: 86%

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ROLE OF MOUSE CYP2E1 IN THEO-HYDROXYLATION OFP-NITROPHENOL: COMPARISON OF ACTIVITIES IN HEPATIC MICROSOMES FROMCYP2E1(-/-) AND WILD-TYPE MICE

Wolf

Wood²,

Bement³

et al. 2004

Drug Metab Dispos

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“…These effects are seen with higher exposure to acetaminophen after oral loading. Caffeine also induces a member of the CYP450 3A family [54,55]. However, acetaminophen is metabolized to a toxic metabolite by CYP450 (3A4).…”

Section: Mechanistic Basis For Drug–drug Interactionsmentioning

confidence: 99%

Alterations of chemotherapeutic pharmacokinetic profiles by drug–drug interactions

Mani¹,

Ghalib²,

Chaudhary³

et al. 2009

Expert Opinion on Drug Metabolism & Toxicology

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Background Drug interactions in oncology are common place and largely ignored as we tolerate high thresholds of ‘toxic’ drug responses in these patients. However, in the era of ‘targeted’ or seemingly ‘less toxic’ therapy, these interactions are more commonly flagged and contribute significantly towards poor ‘quality of life’ and medical fatalities. Objective This review and opinion article focuses on alteration of chemotherapeutic pharmacokinetic profiles by drug interactions in the setting of polypharmacy. The assumption is that the drugs, with changes in their pharmacokinetics, will contribute towards changes in their pharmacodynamics. Methods The examples cited for such drug–drug interactions are culled from published literature with an emphasis on those interactions that have been well characterized at the molecular level. Results Although very few drug interaction studies have been performed on approved oncology based drugs, it is clear that drugs whose pharmacokinetics profiles are closely related to their pharmacodynamics will indeed result in clinically important drug interactions. Some newer mechanisms are described that involve interactions at the level of gene transcription, whereby, drug metabolism is significantly altered. However, for any given drug interaction, there does not seem to be a comprehensive model describing interactions. Conclusions Mechanisms based drug interactions are plentiful in oncology; however, there is an absolute lack of a comprehensive model that would predict drug–drug interactions.

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“…CYP3A exposureinduced P450 3A in primary cultures of human and rat hepatocytes (Kostrubsky et al, 1995;DiPetrillo et al, 2002). In the CYP3A4-expressing HepG2 cell line, incubation with ethanol increased CYP3A4 mRNA level and CYP3A activity in a dose-dependent manner (Feierman et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Chronic ethanol exposure downregulates hepatic expression of pregnane X receptor and P450 3A11 in female ICR mice

Wang

Sun

et al. 2005

Toxicology

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Effect of Caffeine on Acetaminophen Hepatotoxicity in Cultured Hepatocytes Treated with Ethanol and Isopentanol

Cited by 20 publications

References 33 publications

ROLE OF MOUSE CYP2E1 IN THEO-HYDROXYLATION OFP-NITROPHENOL: COMPARISON OF ACTIVITIES IN HEPATIC MICROSOMES FROMCYP2E1(-/-) AND WILD-TYPE MICE

ROLE OF MOUSE CYP2E1 IN THEO-HYDROXYLATION OFP-NITROPHENOL: COMPARISON OF ACTIVITIES IN HEPATIC MICROSOMES FROMCYP2E1(-/-) AND WILD-TYPE MICE

Alterations of chemotherapeutic pharmacokinetic profiles by drug–drug interactions

Chronic ethanol exposure downregulates hepatic expression of pregnane X receptor and P450 3A11 in female ICR mice

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