The 21-aminosteroid U74389G prevents the down-regulation and decrease in activity of CYP1A1, 1A2 and 3A6 induced by an inflammatory reaction.
In vivo, the 21-aminosteroid U74389G prevents the decrease in cytochrome P450 (P450) activity produced by a turpentine-induced inflammatory reaction (TIIR). To investigate the underlying mechanism of action, four groups of rabbits were used, controls receiving or not U74389G, and rabbits with the inflammatory reaction receiving or not U74389G. Hepatocytes were isolated 48h later and incubated for 4 and 24h with the serum of the rabbits. In vivo, the TIIR diminished CYP1A1/2 and 3A6 expression, and enhanced hepatic malondialdehyde (MDA) and nitric oxide (NO*) concentrations (p<0.05). U74389G prevented the increase in MDA, as well as the decrease in CYP1A1/2 amounts and activity, but increased CYP3A6 expression by 40% (p<0.05). In vitro, compared with serum from control rabbits (S(CONT)), incubation of serum from rabbits with TIIR (S(TIIR)) for 4 and 24h with hepatocytes from rabbits with TIIR (H(TIIR)) reduced CYP1A2 and CYP3A6 activity (p<0.05) and increased the formation of NO* and MDA. In rabbits with TIIR pretreated with U74389G, the S(TIIR+U) failed to reduce CYP1A2 activity or to increase MDA, although increased NO* and further reduced CYP3A6 activity. On the other hand, in hepatocytes harvested from rabbits with TIIR pretreated with U74389G, S(TIIR) did not decrease CYP1A2 activity and did not enhance MDA, but still increased NO*. In vitro, the reduction of CYP1A2 and CYP3A6 activity by S(TIIR) is not associated to NF-kappaB activation. In conclusion, U74389G prevents CYP1A1/2 down-regulation and decrease in activity by a double mechanism: hindering the release of serum mediators and by averting intracellular events, effect possibly associated with its antioxidant activity. On the other hand, U74389G up-regulates CYP3A6 but inhibits its catalytic activity.
Taherzadeh
Mehrzad
M
Department of Pharmacology, Faculty of Medicine, University of Montréal, Montréal, Que., Canada.
Fradette
Caroline
C
Bleau
Anne-Marie
AM
Jomphe
Claudia
C
Trudeau
Louis-Eric
LE
du Souich
Patrick
P
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism*; D015536:Down-Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D011281:Pregnatrienes / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D011817:Rabbits; D044967:Serum / Q000378:metabolism; D014425:Turpentine
D011281:Pregnatrienes; D020011:Protective Agents; C074965:U 74389F; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C100638:cytochrome P-450 CYP3A6 (rabbit); D014425:Turpentine