Oxidation of the lignan nordihydroguaiaretic acid

The naturally occurring antioxidant lignan nordihydroguaiaretic acid has been used in traditional medicine to treat a variety of conditions and more recently has been investigated for its anticancer and antimicrobial properties. Nordihydroguaiaretic acid has also been shown to cause kidney toxicity in rats and there is evidence to suggest that chronic nordihydroguaiaretic acid consumption may cause liver toxicity in humans. Nordihydroguaiaretic acid likely undergoes biotransformation to a reactive quinone species, either an ortho-quinone or a para-quinone methide, which is responsible for its toxicity. In an effort to probe the toxicity of nordihydroguaiaretic acid, we oxidized nordihydroguaiaretic acid with both chemical and enzymatic systems and trapped the resultant products with glutathione. The nordihydroguaiaretic acid-glutathione adducts were compared with the products found when nordihydroguaiaretic acid was incubated in rat hepatic microsomes in the presence of glutathione. Glutathione metabolites consistent with ortho-quinone formation were the only oxidation products observed. Control experiments in microsomes however suggested that a majority of the nordihydroguaiaretic acid ortho-quinone glutathione adducts were formed as the result of nordihydroguaiaretic acid autoxidation. We measured the rate of this autoxidation process over a range of pH values and determined that the autoxidation reaction is base-catalyzed. We suggest that caution must be exercised when using nordihydroguaiaretic acid in experiments above pH 7.4 as relatively little of the parent compound may be left in incubations longer than 3 h.