Induction of Hepatic Cytochromes P450 by Dietary 1,4-Bis[2–(3,5–dichloropyridyloxy)] benzene (TCPOBOP) in the B6C3F1 Mouse: Dose-Dependence and Pharmacodynamics

Abstract

The dose-response relationships for hepatic cytochrome P450 (CYP) induction by 1,4-bis(2-[3,5-dichloropyridyloxy])benzene (TCPOBOP) were examined in the male B6C3F1 mouse. TCPOBOP, administered for 14 days at 0.393–96.2 ppm in the diet, caused concentration-dependent induction of hepatic CYP subfamily 2B (C YP2B) protein and of benzyloxy resorufin O-dealkylation. The ED50 values for CYP2B induction, calculated on the basis of immunoreactiveCYP2B protein and benzyloxyresorufln O-dealkylation, were 1.2 ppm and 2.2 ppm dietary TCPOBOP, respectively. The maximal catalytic activities observed were 74–95–fold higher than control values. These induction levels were 2.3–2.6–fold greater than those resulting from exposure of the mice to 500 ppm dietary phenobarbital (a prototypic CYP2B inducer). The EC50 values of TCPOBOP for hepatic CYP2B induction were < 0.3 μmol/1 (serum) and <3.3 μmol/kg (liver). Increases in immunoreactive CYP subfamily 1A and subfamily 3A proteins were also detected, although the maximal induction levels for these subfamilies were relatively low (< threefold, compared to control values). These results indicate that TCPOBOP is an effective CYP2B inducer in the mouse when administered at dietary concentrations well below the no-effect level (12.3 ppm) for the rat.