Synergy of phenobarbital and 3-methylcholanthrene in "superinduction" of cytochrome P-450c mRNA but not enzyme activity.
The combination of phenobarbital and 3-methylcholanthrene in the inductive process of the rat hepatic cytochrome P-450c gene was evaluated. Daily injections of phenobarbital (80 mg/kg, i.p.) had little or no effect on the amount of poly (A)+ RNA encoding cytochrome P-450c, whereas a single injection of 3-methylcholanthrene (25 mg/kg, i.p.) produced a significant accumulation at 15 hr in cytosolic mRNA coding for cytochrome P-450c. Four daily injections of phenobarbital followed by a single dose of 3-methylcholanthrene produced 5-24 times more poly (A)+ RNA coding for P-450c than 3-methylcholanthrene treatment alone. This superinduction of RNA transcripts was also observed for a species coding for cytochrome P-450d, which was increased 3-6 times over 3-methylcholanthrene treatment alone. However, the elevated concentration of transcripts for both the P-450d and P-450c RNA species did not result in an increase in the marker enzyme activity for cytochrome P-450c, 7-ethoxyresorufin O-deethylase. These data implicate a regulatory step in the induction of cytochrome P-450c enzyme activity which must occur at a level beyond transcription.
Iversen
P L
PL
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68105-1065.
Siegel
L I
LI
Rahner
K
K
Bresnick
E
E
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D010088:Oxidoreductases / Q000032:analysis; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains
D012333:RNA, Messenger; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D010634:Phenobarbital