Regional and cellular distribution of CYP2D subfamily members in rat brain

Miksys, Sharon; Rao, Yushu; Sellers, Edward M.; Kwan, Michael; Mendis, Duane B.; Tyndale, Rachel F.

doi:10.1080/004982500406390

Cited by 76 publications

(63 citation statements)

References 36 publications

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“…pyramidal neurons in frontal cortex) (Norris et al, 1996;Miksys et al, 2000;Siegle et al, 2001). The brain region-, and cell-specific induction of CYPs by chronic nicotine treatment also occurs for monkey CYP2B6 (Lee et al, 2006) and CYP2E1 (Joshi and Tyndale, 2006) although the patterns of induction differ for each enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…dextromethorphan), indicating a functional enzyme. Furthermore, in rat brain both mRNA and protein correlate with activity (Miksys et al, 2000). A study demonstrating the initial analgesic effects of codeine due to its in situ metabolism to morphine is additional evidence of brain CYP2D function (Chen et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

“…CYPs are expressed in a number of extrahepatic tissues including the brain. CYP2D has been identified in human (Miksys et al, 2002), dog (Tyndale et al, 1991) and rat (Miksys et al, 2000;Yue et al, 2008) brain tissue. Both, CYP2D mRNA and protein have been surveyed in the human brain (Miksys et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

et al. 2008

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Cytochrome P450 (CYP) 2D6, an enzyme found in the liver and the brain, is involved in the metabolism of numerous centrally acting drugs (e.g. antidepressants, neuroleptics, opiates), endogenous neurochemicals (e.g. catecholamines) and in the inactivation of neurotoxins (e.g. pesticides, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)). Although CYP2D6 is essentially an uninducible enzyme in the liver, we show that smokers have higher CYP2D6 in the brain, especially in the basal ganglia. In order to determine whether nicotine, a component of cigarette smoke, could increase brain CYP2D, African Green monkeys were treated chronically with nicotine (0.05 mg/kg for 2 days, then 0.15 mg/kg for 2 days followed by 0.3 mg/kg for 18 days s.c., b.i.d.). Monkeys treated with nicotine showed significant induction of CYP2D in brain when compared to saline-treated animals as detected by western blotting and immunocytochemistry. No changes in liver CYP2D were observed in nicotine-treated monkeys. Induction was observed in various brain regions including those affected in Parkinson's disease (PD) such as substantia nigra (3-fold, p = 0.01), putamen (2.1-fold, p = 0.001) and brainstem (2.4-fold, p = 0.001), with the caudate nucleus approaching significance (1.6-fold, p = 0.07).Immunocytochemistry revealed that the expression of CYP2D in both saline-and nicotine-treated monkeys is cell-specific particularly in the cerebellum, frontal cortex and hippocampus. These results suggest that monkey brain expresses CYP2D, which is induced in specific cells and brain regions upon chronic nicotine treatment. Smokers, or those using nicotine treatment, may have higher levels of brain CYP2D6 that may result in altered localized CNS drug metabolism and inactivation of neurotoxins.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

et al. 2008

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“…Liver microsomes were prepared as described previously (Miksys et al, 2000), aliquoted into small volumes, and stored at Ϫ80°C until use.…”

Section: Methodsmentioning

confidence: 99%

Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Micu

Miksys

Sellers

et al. 2003

J Pharmacol Exp Ther

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CYP2E1 is an ethanol-and drug-metabolizing enzyme that can also activate procarcinogens and hepatotoxicants and generate reactive oxygen species; it has been implicated in the pathogenesis of liver diseases and cancer. Cigarette smoke increases CYP2E1 activity in rodents and in humans and we have shown that nicotine (0.1-1.0 mg/kg s.c. ϫ 7 days) increases CYP2E1 protein and activity in the rat liver. In the current study, we have shown that the induction peaks at 4 h postnicotine (1 mg/kg s.c. ϫ 7 days) treatment and recovers within 24 h. No induction was observed after a single injection, and 18 days of treatment did not increase the levels beyond that found at 7 days. We found that CYP2E1 is induced by very low doses of chronic (ϫ 7 days) nicotine with an ED 50 value of 0.01 mg/kg s.c.; 0.01 mg/kg in a rat model results in peak cotinine levels (nicotine metabolite) similar to those found in people exposed to environmental tobacco smoke (passive smokers; 2-7 ng/ml). Previously, we have shown no change in CYP2E1 mRNA, and our current mechanistic study indicates that nicotine does not regulate CYP2E1 expression by protein stabilization. We postulated that a nicotine metabolite could be causing the induction but found that cotinine (1 mg/kg ϫ 7 days) did not increase CYP2E1. Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in smokers, passive smokers, and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis or Parkinson's disease).

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“…Liver microsomal membranes were prepared as described previously (Miksys et al, 2000b). Briefly, portions of livers were homogenized manually in 100 mM Tris, pH 7.4, with 0.1 mM EDTA, 0.32 M sucrose, 0.1 mM dithiothreitol on ice.…”

Section: Microsomal Membrane Preparation and Protein Assaymentioning

confidence: 99%

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

Yue

Khokhar

Miksys

et al. 2009

European Journal of Pharmacology

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Alcohol and nicotine are frequently co-used and co-abused, and use of both drugs alone can affect hepatic drug metabolism. We investigated the influences of chronic nicotine treatment and voluntary ethanol intake on the induction of rat hepatic cytochrome P450 (CYP) enzymes that metabolize ethanol and nicotine. Rats were trained to voluntarily drink ethanol (6% v/v, 1 h) with nicotine pretreatment for 10 days. Another group of rats were treated with the same nicotine doses alone. Hepatic CYP2E1, CYP2B1/2 and CYP2D1 proteins were assessed by immunoblotting. Nicotine pretreatment (0.4, 0.8 and 1.2 mg/kg) increased voluntary ethanol intake on day 10 by 1.8, 2.0, and 1.4 fold respectively compared to saline pretreatment (P<0.01-0.3). CYP2E1 was increased 1.7, 1.8, and 1.4 fold by the three doses of nicotine alone (P<0.02-0.21); CYP2E1 levels were increased by voluntary ethanol intake alone and a further 2.4, 2.2, and 1.8 fold by 0.4, 0.8, and 1.2 mg/kg nicotine respectively versus saline pretreatment (P<0.002-0.06). CYP2B1/2 proteins were not induced by nicotine alone, but were increased by 2.2-2.5 fold by ethanol drinking (P<0.05). CYP2E1 (r=0.67, P<0.001) and CYP2B1/2 levels (r=0.49, P=0.007) correlated with alcohol consumption on day 10. There was no change in CYP2D1. Chronic nicotine increased voluntary ethanol intake thereby enhancing CYP2E1 and CYP2B1/2 levels. Thus CYPs are regulated not only directly by nicotine and ethanol, but also indirectly via an increase in the ethanol consumption in the presence of nicotine pretreatment. Together this may contribute to the co-abuse of these drugs and alter the metabolism of clinical drugs and endogenous substrates.

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Regional and cellular distribution of CYP2D subfamily members in rat brain

Cited by 76 publications

References 36 publications

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

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