In vitro Inhibition by Stiripentol of Rat Brain Cytochrome P-450-Mediated Naphthalene Hydroxylation

1. The formation of 1-naphthol from naphthalene was investigated in rat brain 105000g particulate fraction. The reaction showed NADPH dependency and was inhibited by carbon monoxide. Michaelis-Menten kinetics were apparent with Vmax= 0.264pmol/mg protein per min and Km= 22.6μM. 2. Stiripentol, an antiepileptic drug containing a methylenedioxybenzene moiety, proved to be a potent, inhibitor of the reaction, with an IC50 value close to 1 μM under the conditions of study and without preincubation. 3. The inhibitory activity of stiripentol was seen mainly after metabolic activation of the drug. The inhibitory effect appeared progressively when substrate and inhibitor were added together to the incubates, whereas its appearance was more rapid following preincubation of stiripentol.