Hydrogen peroxide supports hepatocyte P450 catalysed xenobiotic/drug metabolic activation to form cytotoxic reactive intermediates.
1. A H2O2 generating system markedly increased the cytotoxicity of catechols, hydroquinone, in isolated hepatocytes, but not in P450 inhibited hepatocytes. 2. H2O2 or 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 H2O2 supported 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. 3. 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 H2O2 formed 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. 4. It is concluded that polyphenolics are oxidised by H2O2/P450 in hepatocytes to form quinone metabolites.
Chan
T S
TS
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Moridani
M
M
Siraki
A
A
Scobie
H
H
Beard
K
K
Eghbal
M A
MA
Galati
G
G
O'Brien
P J
PJ
D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology; D005419:Flavonoids; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D010636:Phenols / Q000633:toxicity*; D011108:Polymers / Q000633:toxicity*; D059808:Polyphenols; D051381:Rats; D015262:Xenobiotics
D005419:Flavonoids; D010636:Phenols; D011108:Polymers; D059808:Polyphenols; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase; D016660:NAD(P)H Dehydrogenase (Quinone); D005978:Glutathione; D004298:Dopamine