Suppression of microsomal cytochrome P450-dependent monooxygenases and mitochondrial oxidative phosphorylation by fullerenol, a polyhydroxylated fullerene C60.
The acute toxicity of fullerenol-1 was determined using mice pretreated intraperitoneally (i.p.) with polyhydroxylated C60 derivatives. The LD50 value of fullerenol-1 was estimated to be 1.2 g/kg. Pretreatments with 0.5 and 1.0 g/kg fullerenol-1 decreased cytochromes P450 and b5 contents, and NADPH-cytochrome P450 reductase, benzo[a]pyrene hydroxylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase activities in liver microsomes. Pretreatments with 0.01 and 0.1 g/kg fullerenol-1 had no effect on these monooxygenases. Additions of fullerenol-1 to mouse liver microsomes suppressed monooxygenases activities toward benzo[a]pyrene, 7-ethoxycoumarin, aniline, and erythromycin with IC50 values of 42, 94, 102 and 349 microM, respectively. Fullerenol-1 exhibited noncompetitive and mixed-type of inhibition in benzo[a]pyrene hydroxylation and 7-ethoxycoumarin O-deethylation, respectively. Additions of fullerenol-1 to rat liver mitochondria resulted in a dose-dependent inhibition of ADP-induced uncoupling and markedly inhibited mitochondrial Mg2+ -ATPase activity with an IC50 value of 7.1 microM. These results demonstrate that fullerenol-1 can suppress the levels of the microsomal enzymes in vivo and decrease the activities of P450-dependent monooxygenase and mitochondrial oxidative phosphorylation in vitro.
Ueng
T H
TH
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, ROC. thueng@ha.mc.ntu.edu.tw
Kang
J J
JJ
Wang
H W
HW
Cheng
Y W
YW
Chiang
L Y
LY
D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002244:Carbon / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity; D016166:Free Radical Scavengers / Q000633:toxicity*; D037741:Fullerenes; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D051381:Rats
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D037741:Fullerenes; C108127:fullerenol; D002244:Carbon; D003577:Cytochrome P-450 Enzyme System; D017301:Ca(2+) Mg(2+)-ATPase