COMPARATIVE PHARMACODYNAMICS OF CYP2B INDUCTION BY DDT, DDE, AND DDD IN MALE-RAT LIVER AND CULTURED RAT HEPATOCYTES

In this study the pharmacodynamics were characterized of rat hepatic c ytochrome P-450 2B (CYP2B) induction by the pesticide DDT [1,1,1-trich loro-2,2-bis(p-chlorophenyl)ethane] and its metabolites DDE [1,1-dichl oro-2,2-bis(p-chlorophenyl)ethylene], which is bioretained, and DDD [1 ,1-dichloro-2,2-bis(p-chlorophenyl)ethane] which is metabolized furthe r and therefore less prone to bioaccumulate. DDT, DDE, and DDD were ea ch found to be pure phenobarbital-type cytochrome P-450 inducers in th e male F344/NCr rat, causing induction of hepatic CYP2B and CYP3A, but not CYP1A. The ED50 values for CYP2B induction (benzyloxyresorufin O- dealkylation) by DDT, DDE, and DDD were, respectively, 103, 88, and gr eater than or equal to 620 ppm in diet (14 d of exposure). The efficac ies (E-max values) for induction of benzyloxyresorufin O-dealkylation by DDT, DDE, and DDD were 24-, 22-, and greater than or equal to 21-fo ld respectively, compared to control values. The potencies of the thre e congeners for CYP2B induction appeared also to be similar, with EC50 values (based on total serum DDT equivalents) of 1.5, 1.8, and greate r than or equal to 0.51 mu M, respectively. The EC50 values based on D DT equivalents in hepatic tissue were 15, 16, and greater than or equa l to 5.9 mu mol/kg liver tissue, respectively. In primary cultures of adult rat hepatocytes, DDT, DDE, and DDD each displayed ability to ind uce total cellular RNA coding for CYP2B (ED50 values of 0.98, 0.83, an d greater than or equal to 2.7 mu M, respectively). These results sugg est that DDT, DDE, and DDD each possess a high degree of intrinsic CYP 2B-inducing ability for rat liver, despite marked differences in biore tention among the congeners.