Effects of interleukin-6 on cytochrome P450-dependent mixed-function oxidases in the rat.
Intravenous treatment of male rats with recombinant human interleukin-6 (rhIL6) at 50, 100 and 200 micrograms/kg (corresponding to 4, 8 and 16 x 10(4) U/animal, respectively) reduced the activities of hepatic microsomal cytochrome P450-dependent monoxygenases to varying degrees. Ethylmorphine-N-demethylase activity fell to 53% of control values, an effect similar to that induced by 2.5 mg/kg Escherichia coli lipopolysaccharide (LPS). Ethoxycoumarin-O-deethylase activity was also sensitive to inhibition, whereas IL6 had little effect on the activities of other P450-dependent enzymes, including ethoxyresorufin-O-deethylase. Pentoxyresorufin dealkylase activity, which is representative of the cytochrome P450 IIB 1/2 subfamily, was unaffected by IL6 whereas LPS reduced it to 33.7% of control values. Another hepatocyte-related parameter, serum concentration of alpha 1-acid glycoprotein (AGP), was increased by up to 3.5-fold over baseline by IL6 and 10-fold by LPS. Recombinant human interleukin-1 beta (rhIL1 beta) (10 micrograms/kg, corresponding to 5 x 10(4) U/rat) and recombinant human tumor necrosis factor alpha (rhTNF) (150 micrograms/kg corresponding to 24 x 10(4) U/rat) were both as potent as LPS (2.5 mg/kg) in increasing serum AGP levels and reducing hepatic microsomal monoxygenase activities. IL6 did not potentiate the effects of rhIL1 beta. Hepatic microsomal glucuronyltransferase activities were little affected by LPS and unaffected by rhIL6. Finally, rhIL6 was more potent after i.p. injection than after i.v. or s.c. injection. These results suggest that the effects of LPS, TNF and IL1 on the mixed-function oxidase system in vivo may be due partly to an induction of IL6 in vivo. The different sensitivities of the enzymes to IL6 but not to IL1 or TNF may be due to the involvement of two distinct mechanisms.
Chen
Y L
YL
Department of Pharmacology, U.R.A. CNRS No. 595, Hôpital Cochin, Paris, France.
Florentin
I
I
Batt
A M
AM
Ferrari
L
L
Giroud
J P
JP
Chauvelot-Moachon
L
L
D000818:Animals; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D015870:Gene Expression / Q000187:drug effects; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000032:analysis*; D009961:Orosomucoid / Q000032:analysis; D010088:Oxidoreductases / Q000032:analysis; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015850:Interleukin-6; D008070:Lipopolysaccharides; D009961:Orosomucoid; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1