Differential induction of mRNA expression of cytochromes P450 (CYP2B1 and CYP1A1/2) by metyrapone in primary rat hepatocyte cultures.
The mRNA expression of members of two cytochrome P450 (CYP) gene subfamilies involved in carcinogen activation, the CYP1A1/2 and CYP2B1 forms, was determined in primary rat hepatocyte cultures in response to metyrapone and to the inducer phenobarbital or 5,6-benzoflavone (BNF), respectively. Incubation of cells with 0.5 mM metyrapone resulted in accumulation of CYP1A1 and CYP1A2 mRNA and in a marked increase in CYP1A-associated enzymatic activity as determined by deethylation of ethoxyresorufin. Metyrapone and phenobarbital in combination acted synergistically in elevation of ethoxyresorufin O-deethylase activity. In hepatocytes treated with metyrapone or with phenobarbital, accumulation of CYP2B1 mRNA levels preceded an increase in CYP2B-associated, pentoxyresorufin O-depentylase activity. However, CYP2B1 mRNA levels were first detectable after 24 hours of treatment with phenobarbital, whereas metyrapone elicited a substantial increase in mRNA levels within 14 hours, suggesting differing mechanisms leading to accumulation of CYP2B1 mRNA under the two inducers.
Aubrecht
J
J
Institute of Pharmacology and Toxicology, University of Göttingen, FRG.
Hirsch-Ernst
K I
KI
Foth
H
H
Kahl
G F
GF
Höhne
M W
MW
D000818:Animals; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016895:Culture Media, Serum-Free; D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; D008797:Metyrapone