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

Abstract

In this study the pharmacodynamics were characterized of rat hepatic cytochrome P450 2B (CYP2B) induction by the pesticide DDT \[1,1,1-trichloro-2,2-bis(p -chlorophenyl) ethane] and its metabolites DDE \[1,1-dichloro-2,2-bis(p -chlorophenyl)ethylene], which is bioretained, and DDD \[1,1-dichloro-2,2-bis(p -chlorophenyl)ethane], which is metabolized further and therefore less prone to bioaccumulate. DDT, DDE, and DDD were each found to be pure phenobarbital-type cytochrome P-450 inducers in the 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 620 ppm in diet (14 d of exposure). The efficacies ( E values) for induction of benzyloxyresorufin O -dealkylation by DDT, max DDE, and DDD were 24-, 22-, and 21-fold, respectively, compared to control values. The potencies of the three congeners for CYP2B induction appeared also to be similar, with EC50 values (based on total serum DDT equivalents) of 1.5, 1.8, and 0.51 mu M, respectively. The EC50 values based on DDT equivalents in hepatic tissue were 15, 16, and 5.9 mumol/kg liver tissue, respectively. In primary cultures of adult rat hepatocytes, DDT, DDE, and DDD each displayed ability to induce total cellular RNA coding for CYP2B (ED50 values of 0.98, 0.83, and 2.7 mu M , respectively). These results suggest that DDT, DDE, and DDD each possess a high degree of intrinsic CYP2B-inducing ability for rat liver, despite marked differences in bioretention among the congeners.