Possible Function of Astrocyte Cytochrome P450 in Control of Xenobiotic Phenytoin in the Brain: In Vitro Studies on Murine Astrocyte Primary Cultures

Meyer, Ralf Peter; Knoth, Rolf; Schiltz, Emil; Volk, Benedikt

doi:10.1006/exnr.2000.7553

Cited by 39 publications

(20 citation statements)

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“…3 Data are from murine hippocampal cell line HN25.1 from postnatal day 21 [91]. 4 Data are from astrocyte primary culture from mice [15]. 4 Phenytoin induces CYP2B9, CYP2C29, and CYP3A4/11/13 in the mouse [11,15].…”

Section: Availability Of Heme Is Essential For Brain P450 Functionmentioning

confidence: 99%

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Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Meyer¹,

Gehlhaus²,

Knoth³

et al. 2007

CDM

130

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Cytochrome P450 (CYP, P450) is the collective term for a superfamily of heme-containing membrane proteins responsible for the metabolism of approximately 70 - 80 % of clinically used drugs. Besides the liver and other peripheral organs, P450 isoforms are expressed in glial cells and neurons of the brain. To enlighten their function and significance is a topic of high interest, as most of the neuroactive drugs used in therapy today are not only substrates, but also inducers of brain P450s with far reaching consequences. First of all, brain P450s are regulated differentially from those in liver. The availability of the prosthetic heme group appears to be essential for correct membrane insertion and enzymatic functionality of brain P450s. Furthermore, although not contributing to body's overall drug metabolism, brain P450s fulfil particular functions within specific cell types of the brain. In astrocytes of brain's border lines P450 isoforms are expressed at very high level. They form a metabolic barrier regulating drugs' influx, modulate blood-flow regulation, and act as signalling enzymes in inflammation. In neurons, however, P450s apparently have different function. In specified brain regions such as hypothalamus, hippocampus and striatum they provide signalling molecules like steroids and fatty acids necessary for neuronal outgrowth and maintenance. Induction of these P450s by neuroactive drugs can alter steroid hormone signalling directly in drug target cells, which may cause clinically relevant side effects like reproductive disorders and sexual or mental dysfunction. The understanding of brain P450 function appears to be of major interest in long-term drug mediated therapy of neurological diseases.

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Section: Availability Of Heme Is Essential For Brain P450 Functionmentioning

confidence: 99%

“…4 Data are from astrocyte primary culture from mice [15]. 4 Phenytoin induces CYP2B9, CYP2C29, and CYP3A4/11/13 in the mouse [11,15]. Phenytoin was applied in a concentration of 80 mg/kg/day in solid nutrition, causing a drug serum level of 15 g / ml.…”

Section: Availability Of Heme Is Essential For Brain P450 Functionmentioning

confidence: 99%

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Meyer¹,

Gehlhaus²,

Knoth³

et al. 2007

CDM

130

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show abstract

“…These compounds have a lipophilic structure that facilitates passing the blood-brain barrier and penetration into the central nervous system (Meyer et al, 2004). The cerebral isoforms CYP2B1, CYP2B10, CYP2C29, CYP3A11, and CYP3A13 have been found to be inducible by antiepileptic drugs (AEDs) such as phenytoin or phenobarbital in rats and mice (Volk et al, 1995;Thuerl et al, 1997;Meyer et al, 2001;Hagemeyer et al, 2003). Therefore, a major endeavor in clinic and research is to understand the underlying molecular mechanisms of drug therapy within the central nervous system to improve present therapeutic strategies.…”

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confidence: 99%

Antiepileptic Drugs Affect Neuronal Androgen Signaling via a Cytochrome P450-Dependent Pathway

Gehlhaus

Schmitt²,

Volk³

et al. 2007

J Pharmacol Exp Ther

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“…The P450 isoforms in brain are localized in defined neuronal or glial cell populations (Volk et al, 1995;Hedlund et al, 1996). Several of the P450s expressed in the brain are inducible by alcohol, neuroleptics, anticonvulsants, and endocrine factors (Volk et al, 1995;Hedlund et al, 1996;Rosenbrock et al, 1999;Meyer et al, 2001;Rosenbrock et al, 2001). …”

mentioning

confidence: 99%