HEPATIC CYTOCHROME-P450 2B INDUCTION BY ETHYL PHENYL-SUBSTITUTED CONGENERS OF PHENOBARBITAL IN THE B6C3F1 MOUSE/

The abilities of structural congeners of phenobarbital to induce immun oreactive hepatic cytochrome P450 2B (CYP2B) protein and associated ca talytic activity (benzyloxyresorufin 0-dealkylation) in the male B6C3F 1 mouse were examined. Interspecies differences in inducing ability we re examined through comparison of the results with induction data obta ined previously with the male F344/NCr rat. The congeners were adminis tered in the diet for 2 weeks at concentrations equimolar to 500 ppm o f the prototype CYP2B inducer, phenobarbital. Of the series of compoun ds tested, phenobarbital was the most effective inducer of benzyloxyre sorufin 0-dealkylation and immunoreactive CYP2B protein, with 2-ethyl- 2-phenylsuccinimide, 5-ethyl-5-phenylhydantoin, primidone, and gluteth imide being only 19-42% as effective. 5-Ethyl-5-phenyloxazolidinedione and the ring-opened and decarboxylated congeners, N(2-ethyl-2-phenyla cetyl)urea and 2-ethyl-2-phenylmalonamide, displayed minimal induction of these catalytic activities. Dose-response experiments performed wi th 5-ethyl-5-phenylhydantoin indicated that the intrinsic CYP2B-induci ng activity of this congener was as great as that of phenobarbital in the mouse, although a fourfold greater dietary concentration of this h ydantoin (2000 ppm) was required to elicit a response equivalent to th at caused by 500 ppm phenobarbital. When extent of induction was relat ed to serum total xenobiotic concentration rather than to administered dietary concentration, the potencies of the two congeners were determ ined to be more similar (58 vs. greater than or equal to 78 mu M for p henobarbital and 5-ethyl-5-phenylhydantoin, respectively).