The nitroxide stable radical tempo prevents metal-induced inhibition of CYP1A1 expression and induction.
Heavy metals are known to provoke oxidative stress in fish liver cells. Because H2O2, OH*- and intracellular superoxide are involved in this oxidation, we investigated the effect of nitroxide radical, 2,2,6,6-tetramethylpiperidinyl-N-oxyl (abbreviated as TEMPO), a cell-permeable agent possessing antioxidant properties, on CYP1A expression in trout (Oncorhynchus mykiss) hepatocytes. 3-methylcholanthrene (3-MC) induced the CYP1A-related EROD activity. This induction was inhibited by concomitant exposure to Cd (II), Cu (II), Pb (II) or Zn (II). CYP1A mRNA levels were also reduced. Simultaneous treatment with 3-MC, a heavy metal and TEMPO suppressed both the inhibition of EROD activity and the decrease of CYP1A mRNA expression. These results suggest a working hypothesis that heavy metals produce multiple oxidative effects, including generation of hydroxyl radicals, which could down-regulate CYP1A1 expression. This metal-induced inhibition was prevented by TEMPO, which might protect trout hepatocytes by scavenging free radicals and thus preventing their inhibitory effects on CYP1A induction and expression.
Risso-de Faverney
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C
Laboratoire de Pharmaco-toxicologie Cellulaire et Moléculaire, Centre de Recherche INRA, Antibes, France.
Lafaurie
M
M
Girard
J P
JP
Rahmani
R
R
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015152:Blotting, Northern; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008670:Metals / Q000494:pharmacology*; D008748:Methylcholanthrene / Q000494:pharmacology; D009499:Neutral Red; D017686:Oncorhynchus mykiss; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis
D000975:Antioxidants; D003497:Cyclic N-Oxides; D008670:Metals; D012333:RNA, Messenger; D009499:Neutral Red; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1; C003959:TEMPO