NADPH:cytochrome P-450(c) reductase: Biochemical characterization in rat brain and cultured neurons and evolution of activity during development

Ghersi-Egea, Jean-François; Minn, Alain; Daval, Jean‐Luc; Jayyosi, Zaid; Arnould, Valérie; Amri, H. Souhaili-El; Siest, Gérard

doi:10.1007/bf00964819

Cited by 31 publications

(12 citation statements)

References 37 publications

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“…The ratio of NADPH-cytochrome P450 reductase to CYP content is less than 1:10 in the liver, whereas this ratio is 1:2 -1:3 in the olfactory epithelium (Reed et al, 1986), as it is in the brain parenchyma (Ghersi-Egea et al, 1989). As the NADPH-cytochrome P450 reductasedependent supply of electrons represents the rate-limiting step of CYP oxidoreductase cycle, the higher relative content of NADPH-cytochrome P450 reductase allows a more efficient catalytic activity (Sarkar, 1992).…”

Section: Olfactory Mucosa ‡mentioning

confidence: 96%

Drug Transport into the Mammalian Brain: The Nasal Pathway and its Specific Metabolic Barrier

Minn¹,

Leclerc²,

Heydel³

et al. 2002

Journal of Drug Targeting

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It is generally accepted that the rate of entry into and distribution of drugs and other xenobiotics within the central nervous system (CNS) depends on the particular anatomy of the brain microvessels forming the blood-brain barrier (BBB), and of the choroid plexus forming the blood-cerebrospinal fluid barrier (CSF), which possess tight junctions preventing the passage of most polar substances. Drug entry to the CNS also depends on the physicochemical properties of the substances, which can be metabolised during this transport to pharmacologically inactive, non-penetrating polar products. Finally, the entry of drugs may be prevented by multiple complex specialized carriers, which are able to catalyse the active transport of numerous drugs and xenobiotics out of the CNS. Nasal delivery is currently considered as an efficient tool for systemic administration of drugs that are poorly absorbed via the oral route, and increasing evidence suggests that numerous drugs and potentially toxic xenobiotics can reach the CNS by this route. This short review summarizes recent knowledge on factors controlling the nasal pathway, focusing on drug metabolising enzymes in olfactory mucosa, olfactory bulb and brain, which should constitute a CNS metabolic barrier.

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Section: Olfactory Mucosa ‡mentioning

confidence: 96%

Drug Transport into the Mammalian Brain: The Nasal Pathway and its Specific Metabolic Barrier

Minn¹,

Leclerc²,

Heydel³

et al. 2002

Journal of Drug Targeting

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“…Partially purified P450 from brain is able to metabolize estrogen (Sugita et al, 1987). Additionally, several groups have shown reductase activity in brain microsomal preparations (Sasame et al, 1977;Ghersi-Egea et al, 1989;Ravindranath et al, 1990).…”

mentioning

confidence: 99%

Reconstitution of the Brain Mixed Function Oxidase System: Purification of NADPH‐Cytochrome P450 Reductase and Partial Purification of Cytochrome P450 from Whole Rat Brain

Bergh¹,

Strobel

1992

Journal of Neurochemistry

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NADPH-cytochrome P450 reductase was purified to apparent homogeneity and cytochrome P450 partially purified from whole rat brain. Purified reductase from brain was identical to liver P450 reductase by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot techniques. Kinetic studies using cerebral P450 reductase reveal Km values in close agreement with those determined with enzyme purified from rat liver. Moreover, the brain P450 reductase was able to function successfully in a reconstituted microsomal system with partially purified brain cytochrome P450 and with purified hepatic P450c (P450IA1) as measured by 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation. Our results indicate that the reductase and P450 components may interact to form a competent drug metabolism system in brain tissue.

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“…Even if the cerebral tissue possesses relatively low levels of microsomal CYP-dependent activities (Walther et al, 1987;Perrin et al, 1990;Ravindranath and Boyd, 1995), several xenobiotic-metabolizing CYP isoforms, among them CYPIA, CYP2B and CYP2E, are expressed in cerebral mitochondria (Bhagwat et al, 2000). Moreover, the brain expresses relatively high amounts of NADPH-cytochrome P450 reductase (Ghersi-Egea et al, 1989;Ravindranath et al, 1990), possibly triggering a high NADPH-dependent production of superoxide when metabolizing drugs able to cross the blood-brain barrier and to undergo NADPH-dependent monoelectronic transfer (Lagrange et al, 1994). Accordingly, we recently presented evidence for a superoxide-promoted increase of the permeability of a in vitro model of the BBB (Lagrange et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…As rat brain microsornes contain both NADPH-cytochrome P450 reductase and CYP (Ghersi-Egea et al, 1989), we preincubated microsomes with 10 ~M menadione in the presence of NADPH for up to 30 min, and started CYP activity measurements immediately after. A strong, time-dependent inhibition of both BROD and EROD activities was observed in these conditions (Fig.…”

Section: Effects Of Preincubation With Menadione On Brod and Erod Actmentioning

confidence: 99%

Inhibition of rat brain microsomal cytochrome P450-dependent dealkylation activities by an oxidative stress

Lagrange¹,

El-Bachá

Netter³

et al. 2001

neurotox res

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There is increasing evidence that an oxidative stress not only alters cellular lipids and nucleic acids, but also numerous proteins. This oxidation results in alterations of some cellular functions, either by reversible modifications allowing a post-transcriptional regulation of enzyme activities or receptor affinities, or by irreversible modifications of the protein, triggering its inactivation and destruction. In the present work, we examined the effects of an experimental oxidative stress on rat brain microsomal cytochrome P450-dependent dealkylation activities. For that purpose, superoxide anions were produced either by the NADPH-dependent redox cycling of a quinine, menadione, or by the addition of apomorphine, which produces by autoxidation both superoxide anions and apomorphine-derived quinones. The inhibition of brain cytochrome P450-dependent alkoxyresorufin O-dealkylase activities was dependent on both menadione or apomorphine concentrations. Simultaneously, an increase of microsomal carbonyl groups was recorded. Immunoblotting characterization of brain microsomal oxidized protein was carried out, using antibodies raised against 2,4-dinitrophenylhydrazine as a reagent of protein carbonyl groups, and a revelation by a chemiluminescence method. We observed an increase in cerebral CYP1A protein oxidation, related to menadione concentration, suggesting that oxidation of cytochrome P450 protein may result in its catalytic inactivation.

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NADPH:cytochrome P-450(c) reductase: Biochemical characterization in rat brain and cultured neurons and evolution of activity during development

Cited by 31 publications

References 37 publications

Drug Transport into the Mammalian Brain: The Nasal Pathway and its Specific Metabolic Barrier

Drug Transport into the Mammalian Brain: The Nasal Pathway and its Specific Metabolic Barrier

Reconstitution of the Brain Mixed Function Oxidase System: Purification of NADPH‐Cytochrome P450 Reductase and Partial Purification of Cytochrome P450 from Whole Rat Brain

Inhibition of rat brain microsomal cytochrome P450-dependent dealkylation activities by an oxidative stress

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