Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Meyer, Ralf Peter; Gehlhaus, Marcel; Knoth, Rolf; Volk, Benedikt

doi:10.2174/138920007780655478

Cited by 130 publications

(101 citation statements)

References 78 publications

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“…Brain CYPs are highly inducible, and are often induced differently from their hepatic forms Tyndale 2004, 2006;Meyer et al, 2007). For example, nicotine induces rat CYP2B1 in the brain but not in the liver (Miksys et al, 2000), and ethanol induces rat CYP2B1 in the liver but not in the brain (Schoedel et al, 2001).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Most of the drug-metabolizing forms are expressed at high levels in the liver, but many also show a widespread pattern of extrahepatic distribution (Guengerich, 2005). Several members of families CYP1-CYP3 have been reported in human brain [reviewed in Meyer et al (2007) and Dutheil et al (2010)] and the importance of these P450s in the metabolism of endogenous compounds in the brain and their potential role in normal neurologic function and disease have been highlighted recently (Strobel et al, 2001;Haining and Nichols-Haining, 2007;Meyer et al, 2007;Niwa et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

et al. 2013

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Cytochrome P450 enzymes are responsible for the metabolism of most commonly used drugs. Among these enzymes, CYP3A forms mediate the clearance of around 40-50% of drugs and may also play roles in the biotransformation of endogenous compounds. CYP3A forms are expressed both in the liver and extrahepatically. However, little is known about the expression of CYP3A proteins in specific regions of the human brain. In this study, form-selective antibodies raised to CYP3A4 and CYP3A5 were used to characterize the expression of these forms in the human brain. Both CYP3A4 and CYP3A5 immunoreactivity were found to varying extents in the microsomal fractions of cortex, hippocampus, basal ganglia, amygdala, and cerebellum. However, only CYP3A4 expression was observed in the mitochondrial fractions of these brain regions. Nterminal sequencing confirmed the principal antigen detected by the anti-CYP3A4 antibody in cortical microsomes to be CYP3A4. Immunohistochemical analysis revealed that CYP3A4 and CYP3A5 expression was primarily localized in the soma and axonal hillock of neurons and varied according to cell type and cell layer within brain regions. Finally, analysis of the frontal cortex of chronic alcohol abusers revealed elevated expression of CYP3A4 in microsomal but not mitochondrial fractions; CYP3A5 expression was unchanged. The site-specific expression of CYP3A4 and CYP3A5 in the human brain may have implications for the role of these enzymes in both normal brain physiology and the response to drugs.

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“…Although total P450 content in the human and rodent brain is generally significantly lower than that in the liver (Warner et al, 1988;Bhamre et al, 1992;Volk et al, 1995), recent evidence from rat studies demonstrates that P450-mediated metabolism in the brain can contribute significantly to neurotoxicity (Khokhar and Tyndale, 2012;Zhou et al, 2013). These data coupled with reports that P450 expression in the brain may vary between anatomic regions of the brain (Warner et al, 1988;Dutheil et al, 2009) have led to growing interest in the putative role of brain P450s in determining sensitivity and response to neurotoxic compounds via modulation of local metabolite levels (Meyer et al, 2007;Ferguson and Tyndale, 2011;Ravindranath and Strobel, 2013).Rodents are important models for studying the relative influence of brain versus liver P450s on neurotoxicity; however, most of our knowledge of P450 expression in the rodent brain is derived from studies of whole brain homogenates, and there is a paucity of data on regional P450 expression in the rodent brain. Additional questions include whether the well known sex-and species-specific differences in hepatic P450 expression extend to the brain, and whether P450s in the brain respond to classic inducers of hepatic P450 expression.…”

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confidence: 99%

Cytochrome P450 mRNA Expression in the Rodent Brain: Species-, Sex-, and Region-Dependent Differences

Stamou

Kania-Korwel

et al. 2013

Drug Metab Dispos

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Cytochrome P450 (P450) enzymes play a critical role in the activation and detoxication of many neurotoxic chemicals. Although research has largely focused on P450-mediated metabolism in the liver, emerging evidence suggests that brain P450s influence neurotoxicity by modulating local metabolite levels. As a first step toward better understanding the relative role of brain P450s in determining neurotoxic outcome, we characterized mRNA expression of specific P450 isoforms in the rodent brain. Adult mice (male and female) and rats (male) were treated with vehicle, phenobarbital, or dexamethasone. Transcripts for CYP2B, CYP3A, CYP1A2, and the orphan CYP4X1 and CYP2S1 were quantified in the liver, hippocampus, cortex, and cerebellum by quantitative (real-time) polymerase chain reaction. These P450s were all detected in the liver with the exception of CYP4X1, which was detected in rat but not mouse liver. P450 expression profiles in the brain varied regionally. With the exception of the hippocampus, there were no sex differences in regional brain P450 expression profiles in mice; however, there were marked species differences. In the liver, phenobarbital induced CYP2B expression in both species. Dexamethasone induced hepatic CYP2B and CYP3A in mice but not rats. In contrast, brain P450s did not respond to these classic hepatic P450 inducers. Our findings demonstrate that P450 mRNA expression in the brain varies by region, regional brain P450 profiles vary between species, and their induction varies from that of hepatic P450s. These novel data will be useful for designing mechanistic studies to examine the relative role of P450-mediated brain metabolism in neurotoxicity. IntroductionThe cytochrome P450 (P450) superfamily is a diverse group of enzymes that catalyze the oxidative metabolism of not only endogenous substrates but also xenobiotics, including environmental contaminants of significant public health concern that target the nervous system, including polychlorinated biphenyls, polybrominated diphenyl ethers, and organophosphorus pesticides (Ariyoshi et al., 1995;Foxenberg et al., 2007;Erratico et al., 2013;Feo et al., 2013). Biotransformation of these compounds by P450s can result in bioactivation or detoxication, and the balance between these activities influences the bioeffective dose, and thus the neurotoxic outcome, following environmental exposures, as shown in studies of humans and animal models (Foxenberg et al., 2007;Curran et al., 2011;Kim et al., 2011;Crane et al., 2012;Khokhar and Tyndale, 2012).Much of the research effort to characterize P450-mediated metabolism of neurotoxic compounds has focused on the liver. However, it is now evident that P450s are expressed in a number of extrahepatic tissues, including brain (Ding and Kaminsky, 2003;Ferguson and Tyndale, 2011). Although total P450 content in the human and rodent brain is generally significantly lower than that in the liver (Warner et al., 1988;Bhamre et al., 1992;Volk et al., 1995), recent evidence from rat studies demonstrates that P45...

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Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Cited by 130 publications

References 78 publications

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

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

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

Cytochrome P450 mRNA Expression in the Rodent Brain: Species-, Sex-, and Region-Dependent Differences

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