Assessing Exposure to Lignans and Their Metabolites in Humans

Phytoestrogens occur naturally in plants and are structurally similar to mammalian estrogens. The lignans are a class of phytoestrogen and can be metabolized to the biologically active enterolignans, enterodiol, and enterolactone by a consortium of intestinal bacteria. Secoisolariciresinol diglucoside (SDG), a plant lignan, is metabolized to enterodiol and, subsequently, enterolactone. Matairesinol, another plant lignan, is metabolized to enterolactone. Other dietary enterolignan precursors include lariciresinol, pinoresinol, syringaresinol, arctigenin, and sesamin. Enterolignan exposure is determined in part by intake of these precursors, gut bacterial activity, and host conjugating enzyme activity. A single SDG dose results in enterolignan appearance in plasma 8�10 h later, a timeframe associated with colonic bacterial metabolism and absorption. Conjugation of enterolignans with sulfate and glucuronic acid occurs in the intestinal wall and liver, with the predominant conjugates being glucuronides. Controlled feeding studies have demonstrated dose-dependent urinary lignin excretion in response to flaxseed consumption (a source of SDG); however, even in the context of controlled studies, there is substantial inter-individual variation in plasma concentrations and urinary excretion of enterolignans. The complex interaction between colonic environment and external and internal factors that modulate it likely contribute to this variation. Knowledge of this field, to date, indicates that understanding the sources of variation and measuring the relevant panel of compounds are important in order to use these measures effectively in evaluating the impact of lignans on human health. (Authors abstract)
The relationship between phytoestrogen exposure and disease risk has received substantial attention in the last decade. However, measuring exposure to phytoestrogens in human populations remains a challenging task. Reliable methods for measuring exposure to lignans are needed to assess their safety and efficacy in humans. Observational and intervention studies in humans have suggested that lignin consumption is associated with favorable effects on hormone levels and metabolism, and reductions in risk of cardiovascular disease, osteoporosis, diabetes, and renal disease. Inverse associations between urine or serum levels or dietary intakes of lignans and breast cancer risk also have been reported in some, but not all. Inverse associations have been reported between lignan consumption and cancers of the endometrium, ovaries, and thyroid. In this review, sources of plant lignans are assessed, the intestinal bacterial and human metabolism of lignans described, and factors that influence lignan metabolism and exposure in humans discussed.  The review indicates that plant lignans are metabolized by the enterolignans END and ENL. Substantial interindividual differences in their metabolism occur, even under controlled dietary conditions, but the reasons for such variation and the ultimate impact this may have on human health have not been determined. The overall level of lignan exposure that is important in relation to health and disease is not known. In order to evaluate the safety and efficacy of lignans in humans, the authors suggest that a better understanding of the factors that affect overall exposure to lignans is required, by: (1) establishing more comprehensive dietary databases to estimate plant lignin exposure in population-based studies; (2) identifying the variables that influence plant lignan metabolism by intestinal bacteria; (3) determining the biologic importance of the Phase I oxidative products relative to the parent enterolignans; (4) evaluating the impact of genetic polymorphisms in the Phase II enzymes and efflux proteins on elimination of enterolignans; and (5) developing approaches that integrate gut microbial metabolism with microbial fingerprinting techniques to elucidate the role of the gut bacterial community in lignan metabolism. (Editors comments)