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Suppression of microsomal cytochrome P450-dependent monooxygenases and mitochondrial oxidative phosphorylation by
1Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, ROC. thueng@ha.mc.ntu.edu.tw
Abstract:
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.
Insights
Fullerenol-1, a polyhydroxylated C60 derivative, shows acute toxicity with an LD50 of 1.2 g/kg in mice. It suppresses liver microsomal enzymes and mitochondrial oxidative phosphorylation, indicating potential in vivo and in vitro effects.
Area of Science:
- Toxicology
- Nanomaterial Science
- Biochemistry
Background:
- Polyhydroxylated C60 derivatives, like fullerenol-1, are nanoparticles with potential biological applications.
- Understanding the toxicological profile of fullerenol-1 is crucial for assessing its safety and potential uses.
Purpose of the Study:
- To determine the acute toxicity of fullerenol-1.
- To investigate the in vivo and in vitro effects of fullerenol-1 on liver microsomal enzymes and mitochondrial function.
Main Methods:
- Acute toxicity testing in mice to determine LD50.
- In vivo pretreatment studies with varying doses of fullerenol-1.
- In vitro studies assessing the impact of fullerenol-1 on liver microsomes and mitochondria.
- Enzyme activity assays for cytochrome P450, NADPH-cytochrome P450 reductase, and various monooxygenases.
- Mitochondrial assays including ADP-induced uncoupling and Mg2+-ATPase activity.
Main Results:
- The LD50 of fullerenol-1 was estimated at 1.2 g/kg in mice.
- High-dose pretreatment (0.5 and 1.0 g/kg) with fullerenol-1 decreased hepatic microsomal enzyme content and activity.
- Fullerenol-1 inhibited monooxygenase activities in vitro and suppressed mitochondrial oxidative phosphorylation and Mg2+-ATPase activity.
Conclusions:
- Fullerenol-1 exhibits acute toxicity and can suppress microsomal enzyme levels in vivo.
- The compound demonstrates inhibitory effects on P450-dependent monooxygenases and mitochondrial oxidative phosphorylation in vitro.
- These findings highlight the potential biological activity and toxicological implications of fullerenol-1.