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 cytochrome P-450 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 > or = 620 ppm in diet (14 d of exposure). The efficacies (Emax values) for induction of benzyloxyresorufin O-dealkylation by DDT, DDE, and DDD were 24-, 22-, and > or = 1-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 > or = 0.51 microM, respectively. The EC50 values based on DDT equivalents in hepatic tissue were 15, 16, and > or = 5.9 micromol/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 > or = 2.7 microM, 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.
Nims
R W
RW
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland, USA. rnims@mabioservices.com
Lubet
R A
RA
Fox
S D
SD
Jones
C R
CR
Thomas
P E
PE
Reddy
A B
AB
Kocarek
T A
TA
D000818:Animals; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003634:DDT / Q000494:pharmacology*; D003633:Dichlorodiphenyl Dichloroethylene / Q000494:pharmacology*; D003632:Dichlorodiphenyldichloroethane / Q000494:pharmacology*; D004790:Enzyme Induction; D007306:Insecticides / Q000494:pharmacology*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D007306:Insecticides; D003633:Dichlorodiphenyl Dichloroethylene; D003577:Cytochrome P-450 Enzyme System; D003634:DDT; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D003632:Dichlorodiphenyldichloroethane