Alteration of delta 9-tetrahydrocannabinol-induced teratogenicity by stimulation and inhibition of its metabolism.

Treatment of pregnant mice with delta 9-tetrahydrocannabinol (THC) significantly increased the incidence of in utero deaths. SKF-525A pretreatment increased the incidence of THC-induced in utero deaths. THC also significantly reduced the body weight of surviving fetuses. Phenobarbital treatment antagonized THC-induced reduction of fetal body weight, but did not reduce resorption rate. Administration of THC, 50 or 200 mg/kg, did not induce fetal anomalies. However, both SKF-525A and phenobarbital treatment potentiated THC-induced cleft palates. SKF-525A treatment plus THC produced 36% cleft palates. Phenobarbital treatment plus THC produced 77% cleft palates. Pretreatments altered the level of tetrahydrocannabinol plus metabolites found in plasma, placenta, fetus and amnionic fluid. In general, SKF-525A increased levels and phenobarbital decreased levels. Two chemically reactive metabolites of THC are proposed, 9,10-epoxyhexahydrocannabinol and an 11-oxo derivative. SKF-525A pretreatment increased the concentration of both of these metabolites. Phenobarbital treatment increased the levels of the proposed 9,10-epoxyhexahydrocannabinol. Possible covalent binding of THC was observed. An active metabolite theory may apply to the teratogenic properties of THC.