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 immunoreactive hepatic cytochrome P450 2B (CYP2B) protein and associated catalytic activity (benzyloxyresorufin O-dealkylation) in the male B6C3F1 mouse were examined. Interspecies differences in inducing ability were examined through comparison of the results with induction data obtained previously with the male F344/NCr rat. The congeners were administered in the diet for 2 weeks at concentrations equimolar to 500 ppm of the prototype CYP2B inducer, phenobarbital. Of the series of compounds tested, phenobarbital was the most effective inducer of benzyloxyresorufin O-dealkylation and immunoreactive CYP2B protein, with 2-ethyl-2-phenylsuccinimide, 5-ethyl-5-phenylhydantoin, primidone, and glutethimide being only 19-42% as effective. 5-Ethyl-5-phenyloxazolidinedione and the ring-opened and decarboxylated congeners, N-(2-ethyl-2-phenylacetyl)urea and 2-ethyl-2-phenylmalonamide, displayed minimal induction of these catalytic activities. Dose-response experiments performed with 5-ethyl-5-phenylhydantoin indicated that the intrinsic CYP2B-inducing activity of this congener was as great as that of phenobarbital in the mouse, although a fourfold greater dietary concentration of this hydantoin (2000 ppm) was required to elicit a response equivalent to that caused by 500 ppm phenobarbital. When extent of induction was related to serum total xenobiotic concentration rather than to administered dietary concentration, the potencies of the two congeners were determined to be more similar (58 vs. > or = 78 microM for phenobarbital and 5-ethyl-5-phenylhydantoin, respectively).
Nims
R W
RW
Chemistry Section, Frederick Cancer Research and Development Center, MD 21702.
Lubet
R A
RA
Diwan
B A
BA
Mellini
D W
DW
Utermahlen
W E
WE
Thomas
P E
PE
D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008617:Mephenytoin / Q000031:analogs & derivatives / Q000633:toxicity; D051379:Mice; D010634:Phenobarbital / Q000031:analogs & derivatives / Q000633:toxicity*; D010636:Phenols / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D010636:Phenols; C014544:ethylphenylhydantoin; D003577:Cytochrome P-450 Enzyme System; D008617:Mephenytoin; D010634:Phenobarbital