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Eur Arch Psychiatry Clin Neurosci (2012) 262:697704 DOI 10.1007/s00406-012-0309-8
ORIGINAL PAPER
Retinoic acid as target for local pharmacokinetic interaction with modanil in neural cells
Julian Hellmann-Regen Karen Gertz
Ria Uhlemann Michael Colla Matthias Endres
Golo Kronenberg
Received: 1 February 2012 / Accepted: 7 March 2012 / Published online: 21 March 2012 Springer-Verlag 2012
Abstract While the biological importance of the cyto-chrome P450 system in the liver is well established, much less is known about its role in the brain and drug interactions at the level of brain cells have hardly been investigated. Here, we show that modanil, a well-known inducer of hepatic CYP enzymes, also increases CYP3A4 expression in human-derived neuron-like SH-SY5Y cells. Upregulation of CYP3A4 by modanil was associated with increased retinoic acid (RA) degradation, which could be blocked by specic CYP3A4 inhibitor erythromycin. In
turn, reduced RA levels in culture medium during modanil treatment resulted in decreased neuronal differentiation of SH-SY5Y cells as assessed by intracellular neurotransmitter concentrations and proliferative activity. Again, this differentiation-impeding effect of modanil on SH-SY5Y cells was antagonized by erythromycin. Similarly, modanil treatment of the murine GL261 glioma cell line resulted in increased proliferative activity. This was associated with upregulation of RA-degrading CYP26A1 in GL261 cells. Taken together, our results indicate that psychopharmacological agents such as modanil may directly act on CYP enzymes in neural tissue. These kinds of drug effects may become highly relevant especially in the context of biomolecules such as RA whose local metabolism in brain is under tight spatial and temporal control.
Keywords Modanil Retinoic acid Cytochrome P450
Differentiation Pharmacokinetics
Introduction
Drug effects on cytochrome P450 enzymes in the liver are a common research subject in neuro- and psychopharmacology. By contrast, the importance of CYP enzymes in adult neural tissue has only rarely been studied and pharmacological interactions occurring locally within the brain have largely been ignored. However, drug effects on cytochrome P450 isozymes in the central nervous system may become highly relevant when molecules are concerned whose metabolism is regulated locally [25]. Retinoic acid (RA), the bioactive derivative of vitamin A, falls into this category. It subserves a critical role in embryonic development as a morphogen and exhibits pleiotropic
J. Hellmann-Regen K. Gertz R. Uhlemann M. Endres
G. KronenbergCenter for Stroke Research Berlin, Berlin,...