Distinct induction profiles of three phenobarbital-responsive mouse liver cytochrome P450 isozymes.
The dose- and time-responses of three liver cytochrome P450 (P450) isozymes to 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and phenobarbital (PB) were studied in DBA/2 mice at activity, protein and mRNA levels. We found that the maximal induction ranged from about 3-fold (P4502a-4/5) and 5-fold (P4502c-x) to more than 50-fold (P4502b-10). Only P4502a-4/5 and associated mRNA displayed a biphasic time-response after TCPOBOP induction: a transient increase occurring 3-8 hr after administration with a subsequent decline at 24 hr before the maximal induction at 72 hr. The changes in P450 isozyme content reflected those in mRNA levels suggesting that the induction by TCPOBOP and PB is controlled largely at pretranslational stages. The isozyme P4502c-x and associated immunoinhibited benzphetamine N-demethylase and testosterone 16 beta-hydroxylase activities were induced half-maximally by 6-30 times smaller doses of TCPOBOP and by three to four times smaller doses of PB than isozymes P4502a-4/5, P4502b-10 or related activities. Furthermore, larger doses of TCPOBOP decreased the expression of P4502c-x to sub maximal levels. Our data show that the three isozymes, although all inducible by TCPOBOP and PB, have distinct dose dependencies and different time-responses to induction. This indicates that the induction by TCPOBOP and PB of P450s belonging even to the same subfamily may proceed by different mechanisms.
Honkakoski
P
P
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Auriola
S
S
Lang
M A
MA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008811:Mice, Inbred DBA; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010634:Phenobarbital / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013250:Steroid Hydroxylases / Q000378:metabolism
D007527:Isoenzymes; D011725:Pyridines; D012333:RNA, Messenger; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C019781:benzphetamine N-demethylase; C025619:steroid 16-beta-hydroxylase; D010089:Oxidoreductases, N-Demethylating; D010634:Phenobarbital