Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture.
Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CYP1A2, CYP2C, CYP2E1, CYP3A, and epoxide hydrolase in primary human hepatocyte cultures. Steady state P-450 and epoxide hydrolase mRNA levels, as well as ethoxyresorufin-O-deethylase and nifedipine oxidation activities, which are mainly supported by CYP1A1/1A2 and CYP3A, respectively, were measured. Interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha were found to be the most potent depressors of P-450 enzymes. After 3 days of treatment, both mRNA levels and enzyme activities were depressed, typically by at least 40%, whatever the cytokine and the enzyme considered. Interferon-gamma also suppressed CYP1A2 and CYP2E1 mRNA levels and ethoxyresorufin-O-deethylase activity but had no effect on CYP3A and epoxide hydrolase mRNAs. In addition, interleukin-4 had the opposite effect, compared with other cytokines, on CYP2E1 mRNA, which was increased up to 5-fold; ethoxyresorufin-O-deethylase and nifedipine oxidation activities were not significantly affected. These results provide the first demonstration that various cytokines act directly on human hepatocytes to affect expression of major P-450 genes and that a wide range of responses can be observed among the enzymes for a given cytokine, suggesting that different regulatory mechanisms may be involved.
Abdel-Razzak
Z
Z
INSERM U 49, Hôpital de Pontchaillou, Rennes, France.
Loyer
P
P
Fautrel
A
A
Gautier
J C
JC
Corcos
L
L
Turlin
B
B
Beaune
P
P
Guillouzo
A
A
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology*; D003864:Depression, Chemical; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000201:enzymology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases