Inhibition of human aromatase complex (CYP19) by antiepileptic drugs.
Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex is the enzyme system that converts androgens to estrogens and consequently an inhibition may induce a hormone imbalance. Twelve antiepileptic drugs, used in mono or polytherapy for the treatment of children, were tested for their ability to inhibit aromatase (CYP19) with commercially available microsomes from transfected insect cells using dibenzylfluorescein as substrate. The drugs inhibiting CYP19 were: lamotrigine, oxcarbazepine, tiagabine, phenobarbital, phenytoin, ethosuximide, and valproate. The inhibitory effects (50% reduction in activity compared to enzymes without inhibitor present) were in the range of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered.
Jacobsen
N W
NW
Section of Toxicology and Environmental Chemistry, Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark. nwj@farma.ku.dk
Halling-Sørensen
B
B
Birkved
F K
FK
D000293:Adolescent; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity*; D001141:Aromatase / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D004359:Drug Therapy, Combination; D006801:Humans; D020128:Inhibitory Concentration 50; D007313:Insecta; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
D000927:Anticonvulsants; D001141:Aromatase