Effects of methylmercury on hypnotic action of hexobarbital, liver hydroxylase and cytochrome P-450 in mice.

The effects of methylmercury hydroxide (MeHgOH) on the hypnotic action of hexobarbital was investigated in adult 129/SvSl mice of both sexes. It was found that there was no sex difference in the response to MeHgOH treatment. The action of MeHgOH was intimately related to the interval between MeHgOH administration and the test of hexobarbital hypnosis. A biphasic effect was observed. An initial dose-dependent prolongation of hexobarbital hypnosis was observed in animals pretreated with MeHgOH 24 h earlier. If the interval was extended from 24 h to 1 week, a shortening of sleeping time was observed in MeHgOH treated animals. The animals recovered from the effects of MeHgOH in 3 weeks. The initial effect of MeHgOH was found closely related to the decrease in the rate of hexobarbital metabolism in the liver through lowering of cytochrome P-450 concentration. On the other hand, the delayed shortening of hexobarbital hypnosis was not related to the rate of hexobarbital metabolism. It is assumed that the delayed effect of MeHgOH on the hexobarbital hypnosis is due to MeHgOH acting on the central nervous system to decrease its sensitivity to hexobarbital via interaction with the barbiturate receptors on the GABA-chloride ionophore complex. In animals exposed in utero to MeHgOH, it was found that the duration of hexobarbital-induced sleeping time was significantly longer in the offsprings tested for hexobarbital hypnosis 3.5 months after birth following prenatal exposure to MeHgOH. Repeated administration of hexobarbital to adult offsprings prenatally exposed to MeHgOH and to control mice shortened hexobarbital sleeping time, however, the maximum shortening capacity was smaller in the treated group. It is concluded that the hypnotic action of hexobarbital in mice can be altered by MeHgOH exposure both prenatally and postnatally. The effects of prenatal exposure to MeHg were observed in adult offsprings, indicating that MeHg may have a functional teratogenic effect on barbiturate-induced hypnosis in the absence of gross anomalies.