Abstract
Nordihydroguaiaretic acid (NDGA) is a major lignan metabolite found in Larrea spp., which are widely used in South America to treat various diseases. In breast tissue, estradiol is metabolized to the catechol estrogens such as 4-hydroxyestradiol (4-OHE2), which have been proposed to be cancer initiators potentially involved in mammary carcinogenesis. Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens to their less toxic methoxy derivatives, such as 4-O-methylestradiol (4-MeOE2). The present study investigated the novel biological activities of NDGA in relation to COMT and the effects of COMT inhibition by NDGA on 4-OHE2-induced cyto- and genotoxicity in MCF-7 human breast cancer cells. Two methoxylated metabolites of NDGA, 3-O-methylNDGA (3-MNDGA) and 4-O-methyl NDGA (4-MNDGA), were identified in the reaction mixture containing human recombinant COMT, NDGA, and cofactors. Km values for the COMT-catalyzed metabolism of NDGA were 2.6 µM and 2.2 µM for 3-MNDGA and 4-MNDGA, respectively. The COMT-catalyzed methylation of 4-OHE2 was inhibited by NDGA at an IC50 of 22.4 µM in a mixed-type mode of inhibition by double reciprocal plot analysis. Molecular docking studies predicted that NDGA would adopt a stable conformation at the COMT active site, mainly owing to the hydrogen bond network. NDGA is likely both a substrate for and an inhibitor of COMT. Comet and apurinic/apyrimidinic site quantitation assays, cell death, and apoptosis in MCF-7 cells showed that NDGA decreased COMT-mediated formation of 4-MeOE2 and increased 4-OHE2-induced DNA damage and cytotoxicity. Thus, NDGA has the potential to reduce COMT activity in mammary tissues and prevent the inactivation of mutagenic estradiol metabolites, thereby increasing catechol estrogen-induced genotoxicities.
Highlights
This article is an open access articleNordihydroguaiaretic acid (NDGA; 4-[4-(3,4-dihydroxyphenyl)-2,3-dimethylbutyl]benzene -1,2-diol) is a catecholic lignan mainly present in the five plant species that comprise Larrea [1]
As NDGA contains a catecholic structure, we investigated whether NDGA is a su
As NDGA contains a catecholic structure, we investigated whether NDGA is a subHPLC-DAD, andWe analyses showedtwo that
Summary
This article is an open access articleNordihydroguaiaretic acid (NDGA; 4-[4-(3,4-dihydroxyphenyl)-2,3-dimethylbutyl]benzene -1,2-diol) is a catecholic lignan mainly present in the five plant species that comprise Larrea [1]. We have previously shown that NDGA-containing extracts of Larrea nitida have phytoestrogenic properties and may be applied as an alternative hormone replacement formulation in postmenopausal women [3]. NDGA has been shown to have a wide range of pharmacological activities, including the inhibition of lipoxygenase activity [4] and estradiol binding to sex steroid-binding protein [5] and the growth of viruses and tumors [6,7]. Despite compelling preclinical proof on the health benefits of NDGA, or Larrea plant-based dieatary products containing NDGA, the major drawback for further clinical development is associated with toxicities, especially in the kidney and liver [9]. Further evaluation is warranted to understand the types of toxicities and adverse outcome pathways associated with NDGA consumption
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