Caffeic acid, chlorogenic acid, and dihydrocaffeic acid metabolism: glutathione conjugate formation.
The antioxidant properties of the dietary dihydroxycinnamic acids [caffeic (CA), dihydrocaffeic (DHCA), and chlorogenic (CGA) acids] have been well studied but little is known about their metabolism. In this article, evidence is presented showing that CA, DHCA, and CGA form quinoids and hydroxylated products when oxidized by peroxidase/H(2)O(2) or tyrosinase/O(2). Mass spectrometry analyses of the metabolites formed with peroxidase/H(2)O(2)/glutathione (GSH) revealed that mono- and bi-glutathione conjugates were formed for all three compounds except CGA, which formed a bi-glutathione conjugate only when GSH was present. In contrast, the metabolism of the dihydroxycinnamic acids by tyrosinase/O(2)/GSH resulted in the formation of only mono-glutathione conjugates. In the absence of GSH, hydroxylated products and p-quinones of CA or CGA were formed by peroxidase/H(2)O(2). DHCA formed a hydroxylated adduct (even though GSH was present), as well as the corresponding p-quinone and dihydroesculetin, an intramolecular cyclization product. NADPH also supported rat liver microsomal-catalyzed CA-, CGA-, and DHCA-glutathione conjugate formation, which was prevented by benzylimidazole, a cytochrome P450 inhibitor. Furthermore, the cytotoxicity of CA, CGA, and DHCA toward isolated rat hepatocytes was markedly enhanced by hydrogen peroxide or cumene hydroperoxide-supported cytochrome P450 and was prevented by benzylimidazole. Cytotoxicity was also markedly enhanced by dicumarol, an NADPH/oxidoreductase inhibitor. These results suggest that dihydroxycinnamic acids were metabolically activated by P450 peroxidase activity to form cytotoxic quinoid metabolites.
Moridani
M Y
MY
Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada M5S 2S2.
Scobie
H
H
Jamshidzadeh
A
A
Salehi
P
P
O'Brien
P J
PJ
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D016227:Benzoquinones / Q000378:metabolism; D002109:Caffeic Acids / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002726:Chlorogenic Acid / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet
D000975:Antioxidants; D016227:Benzoquinones; D002109:Caffeic Acids; C000995:3,4-dihydroxyphenylpropionic acid; D002726:Chlorogenic Acid; C004532:quinone; D005978:Glutathione; C040048:caffeic acid