The Biphasic Effect of DDT and 666 on the Biotransformation of Pentobarbital in vivo

The stimulation and inhibition of pentobarbital biotransformation in mice and rats by a series of chemical agents have been reported in a previous communication. This paper reports the effects of two insecticides, technical DDT and γ-hexachlorocyclohexane (666), on the hepatic pentobarbital metabolism. Prior (2 hours) treatment of mice and rats with DDT (100 mg/kg, P. O.) or 666 (25 mg/kg) confers prolongation of pentobarbital sleeping time upon these animals. This effect is believed to be attributable to alteration of pentobarbital metabolism rather than the central action of these insecticides. In spite of the lower ED₅₀ (dose of pentobarbital for 50% of animals to lose righting reflex) of pentobarbital for the treated mice, these mice woke up at the same brain levels of the hypnotic as the untreated controls. One hour after intravenous administration of pentobarbital, the tissue levels of both the DDT and the 666 treated mice were much higher than the control animals. In vitro experiments employing liver slices or 9000g supernatant of liver homogenate also indicated that the hepatic pentobarbital metabolism was lowered by pretreatment with DDT or 666. Further experiments indicate that when the interval between the administration of the insecticides and the barbiturate in rats was prolonged to 48 hours, however, the duration of the pentobarbital narcosis was shortened. It appears that the effect of these two insecticides on pentobarbital sleeping time is actually biphasic in rats. In mice, the effect of 666 was found to be biphasic, while DDT exhibited predominantly the inhibitory phase. Repeated administrations of DDT (20mg/kg) or 666 (10 mg/kg) to rats also caused shortening of the duration of pentobarbital action and this appeared to be attributable to an increase in liver weight in addition to an enhancement of the activity of the hepatic drug metabolizing enzymes. In rats chronically treated with DDT, prior phenobarbital administration shortened the pentobarbital sleeping time still further, while in rats treated with 666 chronically, phenobarbital failed to affect the duration of pentobarbital action. Both DDT and 666 treatment markedly increased the urinary excretion of ascorbic acid in rats. In this aspect, the effect of a single dose (25mg/kg, p. o.)of 666 lasted more than 25 days, while the effect of a dose of DDT (50 mg/kg) disappeared the next day.