STRUCTURE-FUNCTION-RELATIONSHIPS OF THE DIETARY ANTICARCINOGEN ELLAGIC ACID

Ellagic acid is a complex planar molecule which demonstrates a variety of anticarcinogenic activities. Ellagic acid has been shown to inhibi t the CYP1A1-dependent activation of benzo[a]pyrene; to bind to and de toxify the diolepoxide of benzo[a]pyrene; to bind to DNA and reduce th e formation of O-6-methylguanine by methylating carcinogens; and to in duce the phase II detoxification enzymes glutathione S-transferase Ya and NAD(P)H:quinone reductase, Chemical analogs of ellagic acid were s ynthesized to examine the relationship between the hydroxyl and lacton e groups of the ellagic acid molecule and its different anticarcinogen ic activities, These studies demonstrated that both the 3-hydroxyl and the 4-hydroxyl groups were required for ellagic acid to directly deto xify the diolepoxide of benzo[a]pyrene, while only the 4-hydroxyl grou ps were necessary for ellagic acid to inhibit CYP1A1-dependent benzo[a ]pyrene hydroxylase activity, Induction of glutathione S-transferase Y a and NAD(P):quinone reductase required the lactone groups of ellagic acid, but the hydroxyl groups were not required for the induction of t hese phase II enzymes, In addition, the lactone groups, but not the hy droxyl groups, were required for the analogs to reduce the carcinogen- induced formation of O-6-methylguanine. Thus, different portions of th e ellagic acid molecule are responsible for its different putative ant icarcinogenic activities.