SUPPRESSION OF MICROSOMAL CYTOCHROME P450-DEPENDENT MONOOXYGENASES AND MITOCHONDRIAL OXIDATIVE-PHOSPHORYLATION BY FULLERENOL, A POLYHYDROXYLATED FULLERENE C-60

The acute toxicity of fullerenol-1 was determined using mice pretreate d intraperitoneally (i.p.) with polyhydroxylated C-60 derivatives. The LD50 value of fullerenol-1 was estimated to be 1.2 g/kg. Pretreatment s with 0.5 and 1.0 g/kg fuIlerenol-1 decreased cytochromes P450 and b( 5) contents, and NADPH-cytochrome P450 reductase, benzo[a]pyrene hydro xylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythr omycin N-demethylase activities in liver microsomes. Pretreatments wit h 0.01 and 0.1 g/kg fullerenol-1 had no effect on these monooxygenases . Additions of fullerenol-1 to mouse liver microsomes suppressed monoo xygenases activities toward benzo[a]pyrene, 7-ethoxycoumarin, aniline, and erythromycin with IC50 values of 42, 94, 102 and 349 mu M, respec tively. Fullerenol-1 exhibited noncompetitive and mixed-type of inhibi tion in benzo[a]pyrene hydroxylation and 7-ethoxycoumarin O-deethylati on, 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 val ue of 7.1 mu M. These results demonstrate that fullerenol-1 can suppre ss the levels of the microsomal enzymes in vivo and decrease the activ ities of P450-dependent monooxygenase and mitochondrial oxidative phos phorylation in vitro. (C) 1997 Elsevier Science Ireland Ltd.