Signal transduction pathways implicated in the decrease in CYP1A1, 1A2 and 3A6 activity produced by serum from rabbits and humans with an inflammatory reaction.
Incubation of serum from rabbits with a turpentine-induced inflammatory reaction and from humans with an upper respiratory viral infection with hepatocytes from rabbits with a turpentine-induced inflammatory reaction for 4h reduces total cytochrome P450 content and activity of cytochrome P450 isoforms CYP1A1/1A2 and 3A6 without affecting the expression of these proteins. To document the signal transduction pathways implicated in the decrease in CYP1A1/1A2 and 3A6 activity, hepatocytes from rabbits with a turpentine-induced inflammatory reaction were incubated with serum from rabbits with a turpentine-induced inflammatory reaction, serum from individuals with a viral infection and interleukin-6 for 4h in presence of inhibitors of protein kinases. The sera-induced decrease in CYP1A1/1A2 and 3A6 activity was partially prevented by the inhibition of Janus-associated protein tyrosine kinase, double-stranded RNA-dependent protein kinase, protein kinase C, and p42/44 mitogen-activated protein kinase. The serum from rabbits with a turpentine-induced inflammatory reaction increased the phosphorylation of Erk1/2, effect prevented by PD98059 but not by bis-indolylmaleimide, a specific inhibitor of protein kinase C. The results demonstrated that the decrease in total cytochrome P450 content and in CYP1A1/1A2 and 3A6 activity by sera and interleukin-6 involves the activation of protein tyrosine kinases, p42/44 mitogen-activated protein kinase and protein kinase C. Indirect evidence supported that nitric oxide is implicated in the decrease in activity of these enzymes.
Levitchi
Mihaela
M
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada H3C 3J7.
Fradette
Caroline
C
Bleau
Anne-Marie
AM
Michaud
Dorothée
D
Kourylko
Oksana
O
Arcand
Mathieu
M
du Souich
Patrick
P
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology; D015850:Interleukin-6 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010949:Plasma / Q000187:drug effects / Q000201:enzymology*; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D014425:Turpentine
D002352:Carrier Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D020030:Nitric Oxide Donors; C015482:protein kinase modulator; D009599:Nitroprusside; D009569:Nitric Oxide; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C100638:cytochrome P-450 CYP3A6 (rabbit); D014425:Turpentine