ABSENCE OF ENANTIOSELECTIVITY IN THE PHARMACODYNAMICS OF P450 2B INDUCTION BY 5-ETHYL-5-PHENYLHYDANTOIN IN THE MALE-RAT LIVER OR IN CULTURED RAT HEPATOCYTES

To explore the enantioselectivity of ligand interaction with the putat ive phenobarbital receptor, the pharmacodynamics of cytochrome P450 2B (CYP2B) induction by racemic 5-ethyl-5-phenylhydantoin and its two en antiomers were investigated in the male f344/NCr rat and in cultured a dult male rat hepatocytes. Steady-state serum drug concentrations, mea sured following 14 days of administration of the compounds in the diet (0-1320 ppm, n = 3 rats per group), were used as an approximation of intrahepatocellular drug concentration. The serum xenobiotic concentra tions associated with half-maximal hepatic CYP2B induction were 5-10 m u M, based on measurement of pentoxy- or benzyloxyresorufin O-dealkyla tion activities, or immunoreactive CYP2B1 protein. The corresponding p otency values in the hepatocyte culture experiments were 8-12 mu M, ba sed on measurement of total cellular RNA coding for CYP2B1. In both th e in vivo and hepatocyte culture experiments, the potencies for CYP2B induction were essentially equivalent for the racemate and the individ ual enantiomers of 5-ethyl-5-phenylhydantoin. In the case of this comp ound, there would appear to be no enantioselectivity for CYP2B inducti on. this finding may be interpreted as evidence against receptor media tion in the induction of CYP2B activity, although it is also possible that a receptor is involved that does not exhibit enantioselectivity.