Progress in Psychiatry

Michels, Robert; Pm, Marzuk

doi:10.1056/nejm199308263290908

Cited by 46 publications

(30 citation statements)

References 136 publications

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“…Altered levels of CYP2D6 in these microenvironments may significantly influence localized drug metabolism and resulting drug response (Britto and Wedlund, 1992). There is evidence of very poor correlation between drug effect and plasma levels for neuroleptics and antidepressants (Michels and Marzuk, 1993). Localized CNS drug metabolism may contribute to this poor relationship, and this effect may be exacerbated in those exposed to cigarette smoke and/or on nicotine therapy, where they may experience altered therapeutic drug effect.…”

Section: Discussionmentioning

confidence: 99%

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%

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

et al. 2008

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“…6 One explanation for this apparent disconnect may be local brain drug metabolism. A rat model was used to investigate local brain metabolism of propofol, a commonly used anesthetic that varies considerably in its effect among individuals.…”

Section: Drug Efficacymentioning

confidence: 99%

“…[3][4][5] There is a great deal of variation in individual responses to centrally acting drugs, and in some cases the plasma levels of these drugs and/or their metabolites do not predict their therapeutic effect. 6 Drug metabolism by CYPs takes place primarily in the liver, but CYP enzymes are also found in many other tissues, including brain. 7 It is predicted that local brain metabolism of centrally acting drugs at their site of action can influence their therapeutic efficacy independently of liver metabolism, and differences in brain levels of CYP enzymes can contribute to the observed interindividual variation in drug response.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450–mediated drug metabolism in the brain

Miksys

Tyndale

2013

J Psychiatry Neurosci

116

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“…These isozymes can metabolize a vast array of compounds including centrally acting drugs, neurotoxins, neurotransmitters, and neurosteroids (Ekins and Wrighton, 1999;Hiroi et al, 2001;Elbaz et al, 2004;Zanger et al, 2004;Seliskar and Rozman, 2007). Individuals respond differently to centrally acting therapeutic drugs, and their response is not always predicted by circulating drug levels in their plasma (Michels and Marzuk, 1993). Drugs that act on the central nervous system (CNS) may be metabolized in situ in the brain, and alterations in the degree of in situ metabolism may contribute to variation in an individual's response.…”

Section: Introductionmentioning

confidence: 99%

Brain Drug-Metabolizing Cytochrome P450 Enzymes are Active In Vivo, Demonstrated by Mechanism-Based Enzyme Inhibition

Miksys

Tyndale

2008

Neuropsychopharmacol

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Individuals vary in their response to centrally acting drugs, and this is not always predicted by drug plasma levels. Central metabolism by brain cytochromes P450 (CYPs) may contribute to interindividual variation in response to drugs. Brain CYPs have unique regional and cell-type expression and induction patterns, and they are regulated independently of their hepatic isoforms. In vitro, these enzymes can metabolize endogenous and xenobiotic substrates including centrally acting drugs, but there is no evidence to date of their in vivo function. This has been difficult to demonstrate in the presence of hepatically derived metabolites that may cross the blood-brain barrier. In addition, because of the membrane location of brain CYPs and the rate limiting effect of endogenous heme levels on the activity and appropriate membrane insertion of some induced CYPs, it has been unclear whether sufficient cofactors and coenzymes are present for constitutive and induced CYP forms to be enzymatically active. We have developed a method using a radiolabeled mechanism-based inhibitor of CYP2B1, 3 H-8-methoxypsoralen, to demonstrate for the first time that both the constitutive and induced forms of this enzyme are active in situ in the living rat brain. This methodology provides a novel approach to assess the function of enzymes in extrahepatic tissues, where expression levels are often low. Selective induction of metabolically active drug metabolizing enzymes in the brain may also provide ways to control prodrug activation in specific brain regions as a novel therapeutic avenue.

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Progress in Psychiatry

Cited by 46 publications

References 136 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

Cytochrome P450–mediated drug metabolism in the brain

Brain Drug-Metabolizing Cytochrome P450 Enzymes are Active In Vivo, Demonstrated by Mechanism-Based Enzyme Inhibition

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