caa a22 4500 475819101 CHVBK 20180406123817.0 cr unu---uuuuu 170329e20000501xx s 000 0 eng 10.1007/s002280050733 doi (NATIONALLICENCE)springer-10.1007/s002280050733 Modulation of midazolam 1-hydroxylation activity in vitro by neurotransmitters and precursors [Elektronische Daten] [C. Martínez, G. Gervasini, J. A. G. Agúndez, J. A. Carrillo, S. I. Ramos, F. J. García-Gamito, L. Gallardo, J. Benítez] Objective: The aim of this study was to find whether endogenous substances could modulate CYP3A activity. There is evidence that CYP3A, a major phase-I xenobiotic metabolizing enzyme, is present in human brain but, at the present time, endogenous substrates for such an enzyme remain to be identified. A possible linkage between the CYP2D6 enzyme and serotonergic transmission has been recently reported by our group. In the same manner, structurally related enzymes such as CYP3A could also be related to endogenous compounds. Methods: CYP3A activity was measured using the enzyme-specific substrate midazolam in human liver microsomes. Several neurotransmitters, precursors, and their metabolites, corresponding to three different metabolic routes, were assayed as putative modulators of CYP3A enzyme activity. These comprised serotonergic, catecolaminergic, and GABAergic transmitters and precursors. The inhibitory capacity of ketoconazole, a competitive inhibitor of CYP3A, was also analyzed for comparison. Results: The kinetic analysis of the midazolam 1-hydroxylase activity measured in microsomes from five human liver samples indicated K m values (mean ± SD) of 5.8 ± 4.9 μM, and Vmax values of 1.7 ± 1.4 nmol min−1 per mg microsomal protein in all the samples used in the study. Of the 14 substances analyzed, adrenaline, serotonin, and 5-hydroxytriptofol were full inhibitors of CYP3A enzyme activity (Ki values of 42.3, 26.4, and 43 μM, respectively). The remaining substances were weak inhibitors or had no inhibitory effect. Conclusion: Brain CYP3A activity could be modulated by some neurotransmitters and precursors. Springer-Verlag Berlin Heidelberg, 2000 Key words CYP3A nationallicence Metabolism nationallicence Indoleamines nationallicence Martínez C. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut Gervasini G. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut Agúndez J. A. G. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut Carrillo J. A. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut Ramos S. I. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut García-Gamito F. J. Service of General Surgery, INSALUD Hospital Merida, Badajoz, Spain, ES aut Gallardo L. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut Benítez J. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut https://doi.org/10.1007/s002280050733 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050733 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Martínez C. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut NATIONALLICENCE 700 1- Gervasini G. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut NATIONALLICENCE 700 1- Agúndez J. A. G. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut NATIONALLICENCE 700 1- Carrillo J. A. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut NATIONALLICENCE 700 1- Ramos S. I. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut NATIONALLICENCE 700 1- García-Gamito F. J. Service of General Surgery, INSALUD Hospital Merida, Badajoz, Spain, ES aut NATIONALLICENCE 700 1- Gallardo L. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut NATIONALLICENCE 700 1- Benítez J. Department of Pharmacology, Medical School, University of Extremadura, Avda. de Elvas s/n, E-06071 Badajoz, Spain e-mail: jbenitez@unex.es Tel.: +34-924-289458; Fax +34-924-271100, ES aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer