Inhibition of Murine Cytochrome P4501a by Tacrine: In Vitro Studies

Peng, Joanna; Sawchuk, Ronald J.

doi:10.1124/dmd.32.8.805

Cited by 21 publications

(19 citation statements)

References 18 publications

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“…7. A similar hypothesis was proposed for the inactivation of P450 1A by tacrine (Peng et al, 2004). In this study, the authors postulated that a carbon-centered radical or cation intermediate lies on the pathway to secondary carbon hydroxylation and may be responsible for P450 1A inactivation.…”

Section: Discussionmentioning

confidence: 70%

Mechanism of Inactivation of Human Cytochrome P450 2B6 by Phencyclidine

Jushchyshyn¹,

Wahlstrom

Hollenberg³

et al. 2006

Drug Metab Dispos

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ABSTRACT:The mechanism behind the observed inactivation of human P450 2B6 by phencyclidine (PCP) has been evaluated over the past 2 decades. The scope of the current investigation was to contribute to the fundamental knowledge of PCP oxidation and perhaps the mechanism behind P450 inactivation. To study the chemistry of PCP oxidation, we subjected PCP to the Fenton reagent. Under Fenton chemistry conditions, oxidation on all three PCP rings was observed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). When PCP was incubated with the Fenton system in the presence of glutathione (GSH), three GSH-PCP conjugates were identified. Subsequent LC-MS/MS analysis of these conjugates revealed two species that had GSH attached to the cyclohexane ring of PCP and a third conjugate in which GSH was adducted to the piperidine ring. When PCP was incubated across a panel of P450 enzymes, several enzymes, including P450s 2D6 and 3A4, were able to catalyze the formation of the PCP iminium ion, whereas P450s 2B6 and 2C19 were exclusively able to hydroxylate secondary carbons on the cyclohexane ring of PCP. Subsequent mechanistic experiments revealed that only P450s 2B6 and 2C19 demonstrated loss of catalytic activity after preincubation with 10 M PCP. Finally, investigation of P450 2B6 inactivation using structural analogs of PCP revealed that blocking the para-carbon atom on the cyclohexane ring of PCP from oxidation protected the P450 2B6 from inactivation, which suggests that a reactive intermediate generated during the hydroxylation of the cyclohexane ring may be linked to the mechanism of inactivation of P450 2B6 by PCP.The biotransformation of phencyclidine, PCP (Fig. 1), by liver proteins was shown to result in the formation of reactive metabolites leading to P450 inactivation and the formation of covalent adducts with hepatic macromolecules more than 20 years ago (Castagnoli et al., 1997). Originally, covalent binding and enzyme inactivation was thought to occur via alkylation of protein-based nucleophiles by an iminium ion metabolite, M4 (Fig. 1), that arose from the P450-dependent two-electron ␣-carbon oxidation of PCP (Sayre et al., 1997). This hypothesis was supported by the formation of PCP iminium-cyanide adducts and the observation that the presence of cyanide in microsomal incubations protected against the formation of covalent adducts with proteins (Ward et al., 1982b;Hoag et al., 1984). However, subsequent studies demonstrated that the P450 inactivation by the PCP iminium ion (PCP-Im) required the presence of NADPH (Hoag et al., 1984;Osawa and Coon, 1989;Sayre et al., 1991), which inferred that metabolism of PCP beyond the iminium species was required for P450 inactivation.Later, the PCP mechanism-based inactivation of P450 2B6, using purified, recombinant human P450 enzyme, was investigated in great detail (Jushchyshyn et al., 2003). Through a series of experiments, it was shown that P450 2B6 was inactivated via covalent modification of the P450 2B6 apoprotein. Moreover, inclusion of cyanide in the pu...

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Section: Discussionmentioning

confidence: 70%

Mechanism of Inactivation of Human Cytochrome P450 2B6 by Phencyclidine

Jushchyshyn¹,

Wahlstrom

Hollenberg³

et al. 2006

Drug Metab Dispos

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“…The procedures used for the preparation of intestinal microsomal fractions were similar to a reported method (16) with a minor modification. The small intestines of overnight fasted each rat model of diabetes mellitus and their respective control rats (n=4 or 5; each) were cut and washed two times with ice-cold 0.154 M NaCl plus 1 mM dithiothreitol using a squeeze bottle whose tip can fit in the proximal end of the small intestine and the solution was squeezed into the lumen until the content in the lumen was removed.…”

Section: Preparation Of Rat Hepatic or Intestinal Microsomal Fractionsmentioning

confidence: 99%

Telithromycin Pharmacokinetics in Rat Model of Diabetes Mellitus Induced by Alloxan or Streptozotocin

Lee

2008

Pharm Res

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“…The procedures used for the preparation of hepatic [11] and intestinal [12] microsomal fractions were similar to reported methods. Microsomal protein content was measured using a reported method [13].…”

Section: Introductionmentioning

confidence: 99%

Gender differences in ondansetron pharmacokinetics in rats

Yang

Lee

2008

Biopharm & Drug Disp

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It has been reported that ondansetron is primarily metabolized via hepatic CYP2D and 3A1/2 in male Sprague-Dawley rats, and CYP2D1 and 3A2 are male dominant and male specific isozymes, respectively, in rats. Thus, it could be expected that the pharmacokinetics of ondansetron would be changed in male rats compared with those in female rats. Thus, gender-different ondansetron pharmacokinetics were evaluated after its intravenous or oral administration at a dose of 8 mg/kg to male and female Sprague-Dawley rats. After intravenous administration of ondansetron to male rats, the AUC and time-averaged non-renal clearance (Clnr) of the drug were significantly smaller (22.6% decrease) and faster (27.3% increase), respectively, than those in female rats. This probably could be due to faster hepatic blood flow rate in male rats. After oral administration of ondansetron to male rats, the AUC of the drug was also significantly smaller (58.8% decrease) than that in female rats, and this could have been due mainly to increased intestinal metabolism of ondansetron in addition to increased hepatic metabolism of the drug in male rats.

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Inhibition of Murine Cytochrome P4501a by Tacrine: In Vitro Studies

Cited by 21 publications

References 18 publications

Mechanism of Inactivation of Human Cytochrome P450 2B6 by Phencyclidine

Mechanism of Inactivation of Human Cytochrome P450 2B6 by Phencyclidine

Telithromycin Pharmacokinetics in Rat Model of Diabetes Mellitus Induced by Alloxan or Streptozotocin

Gender differences in ondansetron pharmacokinetics in rats

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