Rat brain CYP2B induction by nicotine is persistent and does not involve nicotinic acetylcholine receptors

Khokhar, Jibran Y.; Miksys, Sharon; Tyndale, Rachel F.

doi:10.1016/j.brainres.2010.06.035

Cited by 19 publications

(32 citation statements)

References 32 publications

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“…107 Radioactive CYP2B was detected in increasing amounts over time and was found at higher levels at 24 hours compared with 4 hours after ICV, with no radioactivity detected in the liver at either time point. 106,107 These experiments confirmed that after ICV injection, CYP2B enzymatic activity was inhibited throughout the brain, and that this inhibition persisted for at least 24 hours. These data provided the parameters for inhibiting and inducing CYP2B activity throughout the brain in a living animal, paving the way for studies demonstrating a role for CNSspecific CYP enzymatic activity in drug response.…”

Section: Demonstration Of Brain Cyp Activity In Vivosupporting

confidence: 63%

“…106,107 They also demonstrated that CYP2B is active throughout the brain, and that this mechanism-based inhibitor reaches all parts of the brain after ICV injection, from olfactory bulbs in the anterior to the brainstem in the posterior of the brain. 107 Radioactive CYP2B was detected in increasing amounts over time and was found at higher levels at 24 hours compared with 4 hours after ICV, with no radioactivity detected in the liver at either time point.…”

Section: Demonstration Of Brain Cyp Activity In Vivomentioning

confidence: 97%

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Cytochrome P450–mediated drug metabolism in the brain

Miksys

Tyndale

2013

J Psychiatry Neurosci

117

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Section: Demonstration Of Brain Cyp Activity In Vivosupporting

confidence: 63%

Section: Demonstration Of Brain Cyp Activity In Vivomentioning

confidence: 97%

Cytochrome P450–mediated drug metabolism in the brain

Miksys

Tyndale

2013

J Psychiatry Neurosci

117

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“…Injection of a CYP2B MBI The methods used were modified from previous studies (Khokhar et al, 2010;Miksys and Tyndale, 2009). Briefly, the rats were treated for 7 days with nicotine (1 mg/kg) or saline.…”

Section: Drug Treatmentmentioning

confidence: 99%

“…CYP2Bs metabolize a variety of CNS acting drugs such as propofol (2, 6-diisopropylphenol, Diprivan) and bupropion, and also play a role in the metabolism of neurochemicals and neurotoxins (Ekins et al, 2008). Rat brain, but not liver, CYP2B can be induced by 7-day nicotine treatment, with a return to baseline levels 7 days later (Khokhar et al, 2010). Both basal and induced CYP2B activity can be inhibited selectively in the brain by an injection of a mechanism-based inhibitor (MBI) also known as a suicide inhibitor (Miksys and Tyndale, 2009).…”

Section: Introductionmentioning

confidence: 98%

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

Khokhar

Tyndale

2010

Neuropsychopharmacol

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Drug-metabolizing cytochrome P450 (CYPs) enzymes are expressed in the liver, as well as in extrahepatic tissues such as the brain. Here we show for the first time that drug metabolism by a CYP within the brain, illustrated using CYP2B and the anesthetic propofol (2, 6-diisopropylphenol, Diprivan), can meaningfully alter the pharmacological response to a CNS acting drug. CYP2B is expressed in the brains of animals and humans, and this CYP isoform is able to metabolize centrally acting substrates such as propofol, ecstasy, and serotonin. Rats were given intracerebroventricularly (i.c.v.) injections of vehicle, C8-xanthate, or 8-methoxypsoralen (CYP2B mechanism-based inhibitors) and then tested for sleep time following propofol (80 mg/kg intraperitoneally). Both inhibitors significantly increased sleep-time (1.8- to 2-fold) and brain propofol levels, while having no effect on plasma propofol levels. Seven days of nicotine treatment can induce the expression of brain, but not hepatic, CYP2B, and this induction reduced propofol sleep times by 2.5-fold. This reduction was reversed in a dose-dependent manner by i.c.v. injections of inhibitor. Sleep times correlated with brain (r=0.76, P=0.0009), but not plasma (r=0.24, P=0.39) propofol concentrations. Inhibitor treatments increased brain, but not plasma, propofol levels, and had no effect on hepatic enzyme activity. These data indicate that brain CYP2B can metabolize neuroactive substrates (eg, propofol) and can alter their pharmacological response. This has wider implications for localized CYP-mediated metabolism of drugs, neurotransmitters, and neurotoxins within the brain by this highly variable enzyme family and other CYP subfamilies expressed in the brain.

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“…CYP2B induction within the brain and not in the liver increased brain CYP2B enzyme levels and propofol inactivation. CYP2B can be induced in the brain, but not the liver, by a week of nicotine treatment (Miksys et al, 2000;Khokhar et al, 2010); the treatment resulted in lower propofol levels and reduced sleep times, which could be reversed by an i.c.v. injection of a MBI (Fig.…”

Section: Drug Metabolism Within the Brain Changes Drug Response Inmentioning

confidence: 99%

“Target-Site” Drug Metabolism and Transport

et al. 2015

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The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic b-cell dysfunction and may have a role in how uremic toxins enter pancreatic b-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.

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Rat brain CYP2B induction by nicotine is persistent and does not involve nicotinic acetylcholine receptors

Cited by 19 publications

References 32 publications

Cytochrome P450–mediated drug metabolism in the brain

Cytochrome P450–mediated drug metabolism in the brain

Drug Metabolism within the Brain Changes Drug Response: Selective Manipulation of Brain CYP2B Alters Propofol Effects

“Target-Site” Drug Metabolism and Transport

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