Hydrogen Peroxide Supports Hepatocyte P450 Catalysed Xenobiotic/Drug Metabolic Activation to form Cytotoxic Reactive Intermediates
A H2O2 generating system markedly increased the cytotoxicity of catechols, hydroquinone, in isolated hepatocytes, but not in P450 inhibited hepatocytes.
H2O2or NADPH supported microsomal catalysed GSH conjugate formation with catechols or hydroquinone. Cytochrome P450 inhibitors inhibited conjugate formation. However, superoxide dismutase inhibited NADPH, but did not affect H2O2supported GSH conjugate formation. The conjugate formed with dihydrocaffeic acid was identified as a mono-GSH conjugate indicating that the o-quinone was the major metabolite formed.
Dopamine (a catecholamine) induced cytotoxicity was prevented by inhibitors of monoamine oxidase (MAO) or P450, but was markedly increased by hepatocyte catalase inhibition or NAD(P)H:quinone oxidoreductase inhibition. This suggests that H2O2formed by the mitochondrial metabolism of monoamine oxidase then oxidised dopamine to cytotoxic o-quinone catalysed by P450. Dihydrocaffeic acid cytotoxicity was also increased by the monoamine oxidase substrate tyramine.
It is concluded that polyphenolics are oxidised by H2O2/P450 in hepatocytes to form quinone metabolites.
KeywordsDopamine Superoxide Catalase Catecholamine Quercetin
Unable to display preview. Download preview PDF.
- 4.M. R. Anari, P.D. Josephy, T. Henry, and P. J. O’Brien. Hydrogen peroxide supports human and rat cytochrome P450 1A2-catalysed 2-amino-3-methylimidazo[4,5]quinoline bioactivation to mutagenic metabolites: significance of cytochrome P450 peroxygenase. Chem. Res. Toxicol. 10:582 (1997).PubMedCrossRefGoogle Scholar
- 5.P. J. O’Brien. Hydroperoxides and superoxides in microsomal oxidations. Pharmacol. Ther. A 2:517 (1978).Google Scholar
- 8.E. Dybing, S. D. Nelson, J. R. Mitchell, H. A. Sasame, and J. R. Gillette. Oxidation of α-methyldopa and other catechols by cytochrome P450-generated superoxide anion: possible mechanism of methyldopa hepatitis. Molec. Pharmacyl. 12:911 (1976).Google Scholar
- 9.F. P. Guengerich, A. D. N. Vaz, E. N. Raner, S. J. Pernecky, and M. J. Coon. Evidence for a role of a perferryl-oxygen complex, FeO3+in the N-oxygenation of amines by cytochrome P450 enzymes. Molec. Pharmacol. 51:147 (1997).Google Scholar
- 10.V. D. Samuilov. Photosynthetic oxygen: the role of H2O2. A review. Biochemistry (Moscow). 62:451 (1997).Google Scholar
- 11.P. J. O’Brien. Peroxidases (an invited review). Chem. Biol. Interactions (special edition on Bioactivation).Google Scholar