Influence of urethane and ketamine on rat hepatic cytochrome P450 in vivo

Meneguz, Annarita; Fortuna, Stefano; Lorenzini, Paola; Volpe, Maria Teresa

doi:10.1016/s0940-2993(99)80027-x

Cited by 39 publications

(25 citation statements)

References 23 publications

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“…CYP3A4 has been reported to be a major enzyme catalyzing erythromycin N-demethylation (Wang et al, 1997). In the rat liver, ketamine can decrease CYP3A activity (Meneguz et al, 1999). Thus, the present results further demonstrate that ketamine can reduce CYP3A4 enzyme activity, and the suppressive mechanism occurs at least at a pretranslational level.…”

Section: Discussionsupporting

confidence: 74%

“…Because CYP3A4 is the principal enzyme responsible for ketamine metabolism in the human liver (Hijazi and Boulieu, 2002), we suggest that the ketamine-induced reduction of CYP3A4 enzyme activity may lead to suppression of hepatocyte clearance of this intravenous anesthetic agent. Previous studies showed that ketamine can modulate P450 gene expression (Meneguz et al, 1999;Chan et al, 2005Chan et al, , 2006. Cytoskeletal disruption has been shown to severely impair basal and inducible expressions of human P450 genes (Dvorák et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Chang¹,

Chen²,

Chen

2008

Drug Metab Dispos

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ABSTRACT:Ketamine is an intravenous anesthetic agent often used for inducing and maintaining anesthesia. Cytoskeletons contribute to the regulation of hepatocyte activity of drug biotransformation. In this study, we attempted to evaluate the effects of ketamine on F-actin and microtubular cytoskeletons in human hepatoma HepG2 cells and its possible molecular mechanisms. Exposure of HepG2 cells to ketamine at <100 M, which corresponds to clinically relevant concentrations for 1, 6, and 24 h, did not affect cell viability. Meanwhile, administration of therapeutic concentrations of ketamine obviously interrupted F-actin and microtubular cytoskeletons. In parallel, levels of intracellular calcium concentration-and timedependently decreased after ketamine administration. Analysis by confocal microscopy further revealed that ketamine suppressed calcium mobilization from an extracellular buffer into HepG2 cells.Exposure to ketamine decreased cellular ATP levels. The mitochondrial membrane potential and complex I NADH dehydrogenase activity were both reduced after ketamine administration. Ketamine did not change the production of actin or microtubulin mRNA in HepG2 cells. Consequently, ketamine-caused cytoskeletal interruption led to suppression of CYP3A4 expression and its metabolizing activity. Therefore, this study shows that therapeutic concentrations of ketamine can disrupt F-actin and microtubular cytoskeletons possibly through suppression of intracellular calcium mobilization and cellular ATP synthesis due to downregulation of the mitochondrial membrane potential and complex I enzyme activity. Such disruption of the cytoskeleton may lead to reductions in CYP3A4 activity in HepG2 cells.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Chang¹,

Chen²,

Chen

2008

Drug Metab Dispos

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“…In addition, one cannot rule out pharmacokinetic interactions between nimodipine and ketamine. Nimodipine does not appear to have clear effects on hepatic microsomal enzymes, while ketamine modestly inhibits cytochrome CYP3A (Meneguz et al 1999). As a result, the absence of a potentiation of nimodipine effects by ketamine questions the importance of pharmacokinetic interactions in this study.…”

Section: Discussionmentioning

confidence: 71%

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Krupitsky

2001

Neuropsychopharmacology

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Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/ kg/hr) (Krystal et al. 1999c). In addition, these drugs produce effects in healthy human subjects that resemble aspects of the signs and symptoms of schizophrenia or dissociative disorders (Krystal et al. 25 , NO . 6 Nimodipine-Ketamine Interactions 937 1999a). As a result, ketamine administration may provide a laboratory-based approach that may contribute to the characterization of NMDA receptor contributions to cognitive function and the development of novel pharmacotherapeutic approaches that might ameliorate the consequences of NMDA receptor dysfunction. NMDA receptor antagonists also have ethanol-like behavioral effects in animals and humans (Grant and Colombo 1993;Krystal et al. 1998b;Petrakis et al. 2001). In ethanol dependent patients, ketamine effects were deemed more similar to ethanol effects than they were to the effects of marijuana or cocaine (Krystal et al. 1998b). This observation is consistent with studies indicating that NMDA receptors are among the highest affinity targets of ethanol in the brain, where it produces dose-related uncompetitive antagonism of receptor function (Grant and Lovinger 1995;Lovinger 1997). In animals, the behavioral effects of ethanol have a complex neurobiology, reflecting the interaction of the many component dose-related actions of ethanol in the brain (Green and Grant 1998).Ethanol, relative to the uncompetitive NMDA receptor antagonists phencyclidine and ketamine, has less propensity to produce psychotic symptoms in healthy humans or recovering ethanol-dependent patients (Krystal et al. 1994a;Krystal et al. 1998b;Luby et al. 1959). The limited psychotogenic propensity of ethanol at doses typically associated with human intoxication may reflect the capacity of ethanol facilitation of GABA A receptor function to moderate its NMDA antagonist effects (Grant and Lovinger 1995). Consistent with this hypothesis, some reduction in the perceptual effects of ketamine in healthy human subjects was produced by lorazepam pretreatment (Krystal et al. 1998a). However, preclinical data suggest that the capacity of ethanol to block L-type VSCCs (Crews et al. 1996) may also protect against its psychotogenic potential. In animals, components of the behavioral and discriminative stimulus effects of NMDA antagonists are attenuated by pretreatment with L-type VSCC antagonists (Green and Grant 1999;Green-Jordan and Grant 2000;Popoli et al. 1992;Sukhotina et al. 1999).The current ...

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“…Some researches showed that ethyl carbamate would inhibit CYP3A and increase CYP 1E and 1A activity in rat (Loch et al, 1995;Meneguz et al, 1999). However, influence of extracellular dopamine in rat striatum by volatile anesthetic, halothane has been reported (Adachi et al, 2001), therefore, ethyl carbamate was selected.…”

Section: Pharmacodynamic Effects Of Mdma On Dopamine and 5-ht Levels mentioning

confidence: 99%

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain

Ikeda

Igari

Fuchigami

et al. 2011

European Journal of Pharmacology

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Baseline levels of dopamine and 5-HT in the striatum were 16.5±7.7 and 3.5±1.7 nM (mean ± standard deviation), respectively. After a single administration of MDMA (10 mg/kg, i.p.), a dramatic increase in extracellular dopamine (C max : 36.1-fold vs. baseline) and 5-HT levels (C max : 9.3-fold vs. baseline) was observed. When rats were co-administered with methamphetamine (1, 5 or 10 mg/kg) with MDMA, the dopamine levels induced by MDMA increased in a methamphetamine-dose-dependent manner (C max : 2.5-, 3.5-, and 3.8-fold vs. MDMA). A similar trend was observed in 5-HT levels (C max : 1.1-, 1.3-, and 1.8-fold vs. MDMA). In contrast, ketamine and caffeine showed synergistic effects on the monoamine levels induced by MDMA, whereas the individual administration of either of these compounds did not affect monoamine levels. Ketamine (1, 5 mg/kg) decreased the dopamine levels induced by MDMA (C max : 0.9-and 0.7-fold vs. MDMA) and increased the 5-HT levels induced by MDMA (C max : 1.4-and 1.6-fold vs. MDMA), and co-administration of caffeine (20 2 mg/kg) with MDMA increased dopamine levels (C max : 1.7-fold vs. MDMA). These results suggest that exposure to multiple drugs in addition to MDMA can have neurotoxic effects. 249 words

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Influence of urethane and ketamine on rat hepatic cytochrome P450 in vivo

Cited by 39 publications

References 23 publications

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain

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