The rising use of natural products creates an imperative need for an enhanced awareness of the safety of current and new products making their way into the marketplace. An important example is natural products containing lignans as the principal active component. Despite their structural similarity the lignan of creosote bush can cause hepato- and renal toxicity while the lignans of flaxseed have no reported serious toxicity. This dissertation aimed to investigate the oxidative metabolism of such lignans to determine whether reversible, competitive interactions and/or bioactivation may explain the differences in their apparent toxicity.<p> The first objective was to study the metabolism and bioactivation of nordihydroguaiaretic acid (creosote bush) and secoisolariciresinol (flaxseed). Nordihydroguaiaretic acid metabolism in rat liver microsomes led to the production of three glutathione adducts formed via ortho¬-quinone reactive intermediates. This metabolism was independent of NADPH and thus attributed to autoxidation. Secoisolariciresinol metabolism yielded lariciresinol and no glutathione adducts suggesting an absence of bioactivation to reactive quinone intermediates.<p> The second objective was to study the autoxidation of nordihydroguaiaretic acid. The major autoxidation product was a unique, stable schisandrin-like cyclolignan which was the result of nordihydroguaiaretic acid cyclization. The half-life of nordihydroguaiaretic acid in aqueous solution, pH 7.4, 37ºC is 3.14 hours suggesting the cyclolignan may be responsible for some of the biological effects of nordihydroguaiaretic acid.<p> The third objective was to study the inhibition of cytochrome P450 isoforms 1A2, 2B, 2C11 and 3A by lignans derived from creosote bush and flaxseed. None of the lignans caused irreversible inhibition. Both creosote bush and flaxseed lignans caused reversible inhibition of P450 enzyme activity that involved competitive or mixed-type inhibition, however the inhibition was present at nonphysiologically relevant concentrations. Activation of cytochrome P450 isoforms was also observed at low lignan concentrations. The results suggest that P450-mediated bioactivation or reversible inhibition cannot explain the differences in toxicity noted between the lignans of creosote bush and flaxseed.<p> This work suggests a minimal risk for drug-lignan interactions at P450 enzymes. Further studies are warranted to determine the presence and biological and toxicological role of the nordihydroguaiaretic acid cyclolignan in herbal preparations.

No abstract available. / Thesis (Ph.D.)-University of Natal, Pietermaritzburg, 2002.

Climate change and exotic plant invasions are significant anthropogenic threats to desert community structure and resilience . In the Mojave Desert, the invasive grass red brome (Bromusrubens L) is increasing fire frequency and extent in response to climatic factors. The resilience of this ecosystem will be affected by how plant and animal communities respond to fire. To better understand these dynamics, we studied the environmental factors underlying changes in invasive grass fire regimes in the Mojave Desert and its structural and functional effects on plant and animal communities. Following fire, reestablishment of native vegetation can be preempted by repeated burning associated with the abundant exotic grass red brome. Red brome density is correlated with various climate and landscape variables, but to establish causality, we experimentally assessed germination and growth of red brome. Red brome responded positively to fall precipitation, finer-textured soils, fertile-islands soils, and soils from burned landscapes. Red brome germination is maximized in wet fall periods when adequate water and optimal temperatures overlap . To evaluate landscape responses of pre- and post-fire plant communities and the potential for repeated burning we analyzed vegetation greenness (NDVI) data from 1985-2011 in response to temperature and precipitation. Landscape analysis indicated that the dominance of exotic grasses increases on post-fire landscapes. Following wet fall and winter seasons, high red brome productivity increases fire potential. Without mitigation, the establishment of an invasive-plant-driven fire regime is likely and may drive state transitions from arid shrublands to arid annual grasslands. Potential revegetation of post-fire landscapes will depend at least in part upon the physiological response of surviving vegetation to post-fire landscapes. Plant physiological responses to post-fire landscapes were generally neutral or positive, suggesting that revegetation of post-fire landscapes is not precluded by resource loss associated with fire and may even be enhanced by post-fire conditions. This will likely translate to increased reproductive potential of surviving plants. Alterations to small mammal populations will likely play a role in the reestablishment of vegetation (both native and exotics) as small mammals have strong top-down effects in arid ecosystems. Diversity and species richness responded negatively to burned landscapes as Merriam's kangaroo rat (Dipodomys merriami) increased in abundance while other species practically disappeared from burned landscapes. Merriam's kangaroo rat affects propagule sources through direct consumption, and seed dispersal. Increases in abundance and dominance of Merriam's kangaroo rat will likely alter plant recruitment.