Mechanism of Anticarcinogenic Effects of Myristicin

University Of Texas-Pan American, Edinburg TX

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Abstract

DESCRIPTION (provided by applicant): Data accumulated from epidemiologic studies and experimental investigations strongly suggest that speci fc dietary non-nutrient compounds from vegetables and fruits provide protection against cancer. A compelling body of evidence now indicates that substantial protection against chemical carcinogenesis can be achieved by induction of enzymes involved in carcinogenic metabolism. Although the mechanism of the anticarcinogenic effect of many non-nutrient phytochemicals is not entirely understood, enhancement of detoxification of carcinogenic electrophiles by inducing Phase-II detoxification enzymes such as glutathione S-transferase (GST) and NAD(P)H: quinone reductase (QR) appears to be the single most important component of the mechanisms. GSTs are known to metabolize a number of carcinogens through catalytic and non-catalytic binding mechanisms, thus minimizing the risk of DNA damage. Through redox-cycling, QR mediates the two-electron reduction of quinones leading to the formation of relatively stable hydroquinones, thereby protecting against quinonide-mediated carcinogenesis. Results from animal models and clinical investigations strongly suggest that GSTs play a pivotal role in inhibiting the cellular damage produced by a wide variety of carcinogens and endogenous xenobiotics. A positive correlation between the anticarcinogens, and their ability to induce GST and QR activities, has been observed; more recently an association between decreased GST activity and increased risk of certain cancers has been established. These studies have inspired the search of naturally occurring phytochemicals capable of inducing detoxification enzymes. Our studies and others show that Myristicin, an active constituent of parsley and other plants and vegetables, induces GST activity and inhibits benzo(a)pyrene-induced tumorigenesis in mouse tissues and thus appears to be a potential ehemoprotective agent. Since there are variations in the induction of GSTs due to differences in sex, age, species, and strains of the animals, we propose to carry out a detailed investigation of the induction of GST and QR in order to delineate the potential of myristicin in cancer prevention. Since different classes of GSTs are known to be differentially induced by various agents and that each class of GSTs preferentially metabolizes specific carcinogens, structure-function relationship of the induced enzymes will also be determined. The results of the proposed studies are expected to significantly contribute toward understanding and optimizing the Phase-II defense system by myristicin and developing effective pharmacological and dietary strategies for cancer chemoprevention.