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 inhibit the CYP1A1-dependent activation of benzo[a]pyrene; to bind to and detoxify the diolepoxide of benzo[a]pyrene; to bind to DNA and reduce the formation of O6-methylguanine by methylating carcinogens; and to induce the phase II detoxification enzymes glutathione S-transferase Ya and NAD(P)H:quinone reductase. Chemical analogs of ellagic acid were synthesized to examine the relationship between the hydroxyl and lactone groups of the ellagic acid molecule and its different anticarcinogenic activities. These studies demonstrated that both the 3-hydroxyl and the 4-hydroxyl groups were required for ellagic acid to directly detoxify the diolepoxide of benzo[a]pyrene, while only the 4-hydroxyl groups were necessary for ellagic acid to inhibit CYP1A1-dependent benzo[a]pyrene hydroxylase activity. Induction of glutathione S-transferase Ya and NAD(P):quinone reductase required the lactone groups of ellagic acid, but the hydroxyl groups were not required for the induction of these phase II enzymes. In addition, the lactone groups, but not the hydroxyl groups, were required for the analogs to reduce the carcinogen-induced formation of O6-methylguanine. Thus, different portions of the ellagic acid molecule are responsible for its different putative anticarcinogenic activities.
Barch
D H
DH
Department of Medicine, Lakeside Veterans Affairs Medical Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Rundhaugen
L M
LM
Stoner
G D
GD
Pillay
N S
NS
Rosche
W A
WA
D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000378:metabolism; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D004610:Ellagic Acid / Q000737:chemistry / Q000494:pharmacology*; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis; D006147:Guanine / Q000031:analogs & derivatives / Q000096:biosynthesis; D008658:Inactivation, Metabolic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D016588:Anticarcinogenic Agents; D004610:Ellagic Acid; D001564:Benzo(a)pyrene; D006147:Guanine; C008449:O-(6)-methylguanine; D001579:Benzopyrene Hydroxylase; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase