Interleukin-1beta, interleukin-6, tumour necrosis factor-alpha and interferon-gamma released by a viral infection and an aseptic inflammation reduce CYP1A1, 1A2 and 3A6 expression in rabbit hepatocytes.
Inflammation reduces activity and expression of hepatic cytochrome P450 (P450) and therefore diminishes drug biotransformation. This study aimed to identify the serum mediators triggered by a viral infection and an aseptic inflammation that downregulate P450 isoforms. Incubation of hepatocytes with serum from rabbits with a turpentine-induced inflammation or humans with a viral infection decreased the amount of cytochrome 1A1 (CYP1A1), 1A2 and 3A6 mRNA and apoproteins. By serum fractionation and immuno-neutralization, we showed that in the aseptic inflammation, interleukin-6 and, to a lesser degree, interleukin-1beta are involved in the downregulation of all three isoforms. In serum from humans with a viral infection, interleukin-1beta, interleukin-6, interferon-gamma and tumour necrosis factor-alpha contribute to the downregulation of P450 isoforms. CYP1A1 and 1A2 are regulated by serum mediators at the transcriptional level, while the expression of CYP3A6 appears to be under the control of pre- and posttranscriptional mechanisms.
Bleau
Anne-Marie
AM
Département de Pharmacologie, Faculté de Médecine, Université de Montréal, C.P. 6128, Succ. "Centre ville", Montréal, Québec, Canada H3C 3J7.
Maurel
Patrick
P
Pichette
Vincent
V
Leblond
François
F
du Souich
Patrick
P
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D015152:Blotting, Northern; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D015536:Down-Regulation; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000097:blood / Q000201:enzymology / Q000378:metabolism; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D007375:Interleukin-1 / Q000097:blood / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D011817:Rabbits; D012141:Respiratory Tract Infections / Q000097:blood / Q000201:enzymology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014777:Virus Diseases / Q000097:blood / Q000201:enzymology / Q000378:metabolism*
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C100638:cytochrome P-450 CYP3A6 (rabbit)