Interactions of melatonin with the liver microsomal cytochrome P450 system of rats and humans in vitro and effects on the P450 system and the antioxidative status in rat liver after acute treatment.

In vitro melatonin binds to human and rat liver microsomal cytochrome P-450 (P450) according to a type II substrate. The affinity is similar to that of aniline with a general left-shift. Melatonin interferes with model monooxygenase reactions indicative of different P450 forms in humans and rats (in humans according to the lower specific P450 content less pronounced): the strongest inhibition was found for ethoxyresorufin O-deethylation, indicating the binding to P450 1A, the binding to P450 2B (ethoxycoumarin O-deethylation) was less pronounced, the least inhibition was found for P450 3A (ethylmorphine N-demethylation) reaction. The oxidase function was also inhibited: luminol amplified chemiluminescence was more inhibited than the lucigenin amplified one, hydrogen peroxide formation was inhibited at concentrations higher than 10(-4) M, microsomal NADPH/Fe stimulated lipid peroxidation was inhibited at concentrations higher than 10(5) M. In vivo melatonin prolonged hexobarbital sleeping time in rats in a dose dependent manner (ip. co-administration of 1, 5 and 20 mg/kg b.w. melatonin with 100 mg/kg hexobarbital). Immediately after awakening the animals were sacrificed: a small increase in P450 concentrations cannot be explained, no changes in P450 monooxygenase or oxidase activities nor in microsomal lipid peroxidation or GSH status could be observed.