PMID- 7557864
OWN - NLM
STAT- MEDLINE
DCOM- 19951103
LR  - 20181211
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 22
IP  - 4 Pt 1
DP  - 1995 Oct
TI  - Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, 
      and CYP3A4 in human hepatocytes in primary culture.
PG  - 1143-53
AB  - We have investigated the effect of cytokines, including interleukin-6 (Il-6), 
      interleukin-1 alpha (Il-1 alpha), and tumor necrosis factor-alpha (TNF-alpha), on 
      the inducible expression of cytochrome P450s (CYP) CYP1A1, CYP1A2, and CYP3A4 in 
      human hepatocytes in primary culture. The ability of these cultures to mimic the 
      acute phase response when stimulated with cytokines was evaluated using 
      immunoblotting to measure the production of albumin, ferritin, fibrinogen, and 
      ceruloplasmin. The cytokines exhibited specific patterns of action on the 
      production of these proteins. Albumin was depressed by all the cytokines. In 
      contrast to Il-6 and Il-1 alpha, TNF-alpha reduced the production of fibrinogen 
      and ceruloplasmin but stimulated the production of ferritin. When cells were 
      treated with the CYP inducer alone, large increases in the expression of CYP1A1 
      and CYP1A2 by beta-naphthoflavone and of CYP3A4 by rifampicin were observed at 
      messenger RNA (mRNA) and protein levels, by ribonuclease protection and 
      immunoblotting, respectively. When the cells were treated with the inducer plus 
      cytokines, the induction of mRNA was greatly reduced. Again, specific patterns of 
      action were revealed: Il-6 had the most potent effect on CYP3A4, whereas 
      TNF-alpha was the most potent with CYP1A genes. In all cases, changes at the 
      protein levels paralleled changes at the mRNA levels. In cells preinduced with 
      beta-naphthoflavone or rifampicin, the decay with time of the levels of the 
      CYP1A2 or CYP3A4 proteins, after the removal of the inducer, was not affected by 
      cytokines. We conclude that cytokines strongly repress the inducibility of CYP1As 
      and CYP3A4 genes at a transcriptional or a posttranscriptional level, but affect 
      neither the rate of translation of CYP mRNAs nor the rate of degradation of the 
      CYP proteins in these cultures.
FAU - Muntane-Relat, J
AU  - Muntane-Relat J
AD  - INSERM U 128, CNRS BP5051, Montpellier, France.
FAU - Ourlin, J C
AU  - Ourlin JC
FAU - Domergue, J
AU  - Domergue J
FAU - Maurel, P
AU  - Maurel P
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Benzoflavones)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-1)
RN  - 0 (Interleukin-6)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 6051-87-2 (beta-Naphthoflavone)
RN  - 9001-32-5 (Fibrinogen)
RN  - 9007-73-2 (Ferritins)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.14.14.1 (CYP3A protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
RN  - EC 1.16.3.1 (Ceruloplasmin)
RN  - VJT6J7R4TR (Rifampin)
SB  - IM
MH  - Acute-Phase Reaction
MH  - Base Sequence
MH  - Benzoflavones/pharmacology
MH  - Cells, Cultured
MH  - Ceruloplasmin/biosynthesis
MH  - Cytochrome P-450 CYP1A2
MH  - Cytochrome P-450 CYP3A
MH  - Cytochrome P-450 Enzyme System/biosynthesis/*genetics
MH  - Cytokines/*pharmacology
MH  - Ferritins/biosynthesis
MH  - Fibrinogen/biosynthesis
MH  - *Gene Expression
MH  - Humans
MH  - Interleukin-1/pharmacology
MH  - Interleukin-6/pharmacology
MH  - Liver/*enzymology
MH  - Mixed Function Oxygenases/biosynthesis/*genetics
MH  - Molecular Sequence Data
MH  - Oxidoreductases/biosynthesis/*genetics
MH  - RNA, Messenger/biosynthesis
MH  - Rifampin/pharmacology
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - beta-Naphthoflavone
EDAT- 1995/10/01 00:00
MHDA- 1995/10/01 00:01
CRDT- 1995/10/01 00:00
PHST- 1995/10/01 00:00 [pubmed]
PHST- 1995/10/01 00:01 [medline]
PHST- 1995/10/01 00:00 [entrez]
AID - S0270913995003569 [pii]
PST - ppublish
SO  - Hepatology. 1995 Oct;22(4 Pt 1):1143-53.