Metabolism of (−)-(S)-nicotine by guinea pig and rat brain: identification of cotinine

Jacob, Peyton; Ülgen, Mert; Gorrod, J. W.

doi:10.1007/bf03190975

Cited by 22 publications

(10 citation statements)

References 13 publications

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“…CYP2B6 protein is detectable in human brain tissue (Gervot et al ., 1999; Miksys et al ., 2003) but detectable levels of human brain CYP2A6 protein have not yet been reported. Phenobarbital has been shown to induce in vitro nicotine metabolism in rat brain tissues (Jacob et al ., 1997), likely by induction of rat CYP2B1. The metabolism of other CYP2B substrates is also increased by phenobarbital treatment.…”

Section: Discussionmentioning

confidence: 99%

Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein

Lee

Miksys

Tyndale

2006

British J Pharmacology

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1 CYP2B6 is a drug-metabolizing enzyme expressed in the liver and brain that can metabolize bupropion (Zyban s , a smoking cessation drug), activate tobacco-smoke nitrosamines, and inactivate nicotine. Hepatic CYP2B6 is induced by phenobarbital and induction may affect in vivo nicotine disposition, while brain CYP2B6 induction may affect local levels of centrally acting substrates. We investigated the effect of chronic phenobarbital treatment on induction of in vivo nicotine disposition and CYP2B6 expression in the liver and brain of African Green (Vervet) monkeys. 2 Monkeys were split into two groups (n ¼ 6 each) and given oral saccharin daily for 22 days; one group was supplemented with 20 mg kg À1 phenobarbital. Monkeys were given a 0.1 mg kg À1 nicotine dose subcutaneously before and after treatment. 3 Phenobarbital treatment resulted in a significant, 56%, decrease (P ¼ 0.04) in the maximum nicotine plasma concentration and a 46% decrease (P ¼ 0.003) in the area under the concentration-time curve. Phenobarbital also increased hepatic CYP2B6 protein expression. In monkey brain, significant induction (Po0.05) of CYP2B6 protein levels was observed in all regions tested (caudate, putamen, hippocampus, cerebellum, brain stem and frontal cortex) ranging from 2-fold to 150-fold. CYP2B6 expression was induced in specific cells, such as frontal cortical pyramidal cells and thalamic neurons. 4 In conclusion, chronic phenobarbital treatment in monkeys resulted in increased in vivo nicotine disposition, and induced hepatic and brain CYP2B6 protein levels and cellular expression. This induction may alter the metabolism of CYP2B6 substrates including peripherally acting drugs such as cyclophosphamide and centrally acting drugs such as bupropion, ecstasy and phencyclidine.

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Section: Discussionmentioning

confidence: 99%

Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein

Lee

Miksys

Tyndale

2006

British J Pharmacology

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“…Nicotine enters the brain from the periphery where it is thought to exert its reinforcing effect by acting on brain reward center nicotinic acetylcholine receptors (nAChR) that release dopamine (Di Chiara and Imperato, 1988;Marshall et al, 1997;Rapier et al, 1988). In vitro rat brain membranes are capable of metabolizing nicotine to cotinine (Jacob et al, 1997); however, it is unknown whether altering brain CYP2B activity can significantly influence nicotine brain levels in vivo following peripheral administration. To address this question, nicotine brain levels produced by IV administration of nicotine were measured via in vivo microdialysis following intracerebral ventricular (ICV) injection of C8X.…”

Section: Cyp2b Expression Is Influenced By Both Genetic and Environmementioning

confidence: 98%

Effect of Brain CYP2B Inhibition on Brain Nicotine Levels and Nicotine Self-Administration

Garcia

Coen

Miksys

et al. 2015

Neuropsychopharmacol

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The CYP2B enzyme is expressed in human and rat brain, and metabolizes many CNS-acting drugs. The gene that encodes human CYP2B6 is highly polymorphic, where the variation in brain enzyme levels could result in altered brain drug levels. CYP2B can metabolize nicotine, the main psychoactive ingredient in cigarettes; if altered brain CYP2B activity can influence nicotine brain levels, it could influence nicotine-mediated behaviors. To investigate this, a mechanism-based inhibitor selective for CYP2B, C8-xanthate (20 μg), was administered intracerebroventricularly (ICV) into the brain of rats, and 22 h later, nicotine levels were measured by in vivo microdialysis following nicotine (150 μg/kg intravenous). Brain nicotine levels from 15 to 30 min and the AUC0-45 min were both twofold higher (p<0.05) with C8-xanthate vs vehicle pretreatment; there was no difference in peripheral nicotine levels. Rats were then given ICV pretreatment with C8-xanthate/ASCF and underwent intravenous nicotine self-administration with 3.75-30 μg/kg per infusion dose. C8-xanthate pretreatment increased responding in progressive ratio (15 μg/kg per infusion dose, p<0.05). In a separate cohort, C8-xanthate increased the percentage of rats that acquired self-administration (7.5 μg/kg per infusion dose, p<0.05) from 40% after vehicle pretreatment to 100%, with no difference in peripheral nicotine levels measured at the end of behavior. In a third cohort, C8-xanthate increased the number of sessions required to meet extinction criteria (p<0.05). Together these data demonstrate that the brain CYP2B activity can influence nicotine brain levels and subsequent behaviors independent of hepatic metabolism. This suggests that human smokers with variable CYP2B brain levels could have different nicotine levels and reinforcement, which might have a role in smoking behaviors and dependence.

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“…The latter study administered nicotine intraperitoneally which is similar to intravenous route and releases a large concentration of nicotine to blood concentration as compared to oral route which is extensively metabolized in the liver and cleared in the kidney. [71,72] Other routes of drug administration can also be employed so as to compare the various effects produced on nicotine administration.…”

Section: Discussionmentioning

confidence: 99%

Histomorphological Effects of Nicotine on Selected Parts of the Brain of Adult Wistar Rats

Oyem

Odokuma

2018

Galician med. j.

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Nicotine has been defined as a potent parasympathomimetic alkaloid that accumulates in the roots and leaves of Nightshade family of plants Aim: This study was aimed at evaluating the effects of orally ingested nicotine in the histology of hippocampus, substantia nigra and cerebellum.Materials and Methods: Twenty four adult male Wistar rats (100g – 200g) were randomly divided into 4 groups (group 1 – group 4). Group 1 served as the control group, while groups 2 - 4 were the treated groups. Nicotine was diluted in water and 1ml of the different dosage (2mg/kg/day, 4mg/kg/day and 6mg/kg/day) were administered to the treated groups respectively with the aid of orogastric cannula for 42 days. Animals were euthanized by cervical dislocation at the end of 7, 21 and 42 days so as to demonstrate the dose and time dependant effect of this agent. Brain tissues were harvested, processed and stained using Haematoxylin and eosin according to standard histological techniques. Stained tissue images were captured using digital micrometer eyepiece and cell count was determined using stereological technique.Statistical analysis: Data obtained were subjected to statistical analysis with the use of statistical package for social sciences (SPSS version 20). Significant differences were obtained using One Way Analysis of Variance with a probability of 0.05 (95% confidence limit) and Tukeys post hoc test was further used to determine the mean significant differences between specific groups.Results: Histological findings showed mild, moderate and severe hyperplasia in a dose and time dependant manner. However, observations from quantitative analysisalso revealed a dose and time dependant significant increase in neuronal cell count and cell diameter of the hippocampus, Substantia nigra and cerebellum.Conclusion: This study has demonstrated that oral exposure of Nicotine in rats display proliferative adaptive changes on the hippocampus, substantia nigra and cerebellum in a dose/time dependent manner.

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Metabolism of (−)-(S)-nicotine by guinea pig and rat brain: identification of cotinine

Cited by 22 publications

References 13 publications

Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein

Phenobarbital increases monkey in vivo nicotine disposition and induces liver and brain CYP2B6 protein

Effect of Brain CYP2B Inhibition on Brain Nicotine Levels and Nicotine Self-Administration

Histomorphological Effects of Nicotine on Selected Parts of the Brain of Adult Wistar Rats

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