Incorporation of in vitro techniques for botanicals dietary supplement safety assessment - Towards evaluation of developmental and reproductive toxicity (DART).

As complex mixtures, botanicals present unique challenges when assessing safe use, particularly when endpoint gaps exist that cannot be fully resolved by existing toxicological literature. Here we explore in vitro gene expression as well receptor binding and enzyme activity as alternative assays to inform on developmental and reproductive toxicity (DART) relevant modes of action, since DART data gaps are common for botanicals. Specifically, botanicals suspected to have DART effects, in addition to those with a significant history of use, were tested in these assays.

Safety assessment of mushrooms in dietary supplements by combining analytical data with in silico toxicology evaluation.

Despite growing popularity in dietary supplements, many medicinal mushrooms have not been evaluated for their safe human consumption using modern techniques. The multifaceted approach described here relies on five key principles to evaluate the safety of non-culinary fungi for human use: (1) identification by sequencing the nuclear ribosomal internal transcribed spacer (ITS) region (commonly referred to as ITS barcoding), (2) screening an extract of each fungal raw material against a database of known fungal metabolites, (3) comparison of these extracts to those prepared from grocery store-bought culinary mushrooms using UHPLCPDA-ELS-HRMS, (4) review of the toxicological and chemical literature for each fungus, and (5) evaluation of data establishing presence in-market. This weight-of-evidence approach was used to evaluate seven fungal raw materials and determine safe human use for each.

Epigenetic Manipulation of a Filamentous Fungus by the Proteasome-Inhibitor Bortezomib Induces the Production of an Additional Secondary Metabolite.

The use of epigenetic modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, has been explored increasingly as a technique to induce the production of additional microbial secondary metabolites. The application of such molecules to microbial cultures has been shown to upregulate otherwise suppressed genes, and in several cases has led to the production of new molecular structures. In this study, the proteasome inhibitor bortezomib was used to induce the production of an additional metabolite from a filamentous fungus (Pleosporales).

Labeled content of two furanocoumarins in dietary supplements correlates with neither actual content nor CYP3A inhibitory activity.

Dietary supplements are a multi-billion dollar business, with yearly profit increases. Allegedly safe, these supplements are marketed to a variety of niches, encompassing claims from immune support to weight loss. Six sports nutrition supplements were acquired that were labeled to contain the furanocoumarin(s) bergamottin and/or 6',7'-dihydroxybergamottin (DHB), both of which are potent irreversible inhibitors of the prominent drug metabolizing enzyme cytochrome P450 3A (CYP3A).

Evaluation of culture media for the production of secondary metabolites in a natural products screening program.

Variation in the growing environment can have significant impacts on the quantity and diversity of fungal secondary metabolites. In the industrial setting, optimization of growing conditions can lead to significantly increased production of a compound of interest. Such optimization becomes challenging in a drug-discovery screening situation, as the ideal conditions for one organism may induce poor metabolic diversity for a different organism.

A modified grapefruit juice eliminates two compound classes as major mediators of the grapefruit juice-fexofenadine interaction: an in vitro-in vivo "connect".

The grapefruit juice (GFJ)-fexofenadine interaction involves inhibition of intestinal organic anion transporting polypeptide (OATP)-mediated uptake. Only naringin has been shown clinically to inhibit intestinal OATP; other constituents have not been evaluated. The effects of a modified GFJ devoid of furanocoumarins (~99%) and polymethoxyflavones (~90%) on fexofenadine disposition were compared to effects of the original juice.

Rapid Quantitation of Furanocoumarins and Flavonoids in Grapefruit Juice using Ultra-Performance Liquid Chromatography.

Introduction: Grapefruit juice can increase or decrease the systemic exposure of myriad oral medications, leading to untoward effects or reduced efficacy. Furanocoumarins in grapefruit juice have been established as inhibitors of cytochrome P450 3A (CYP3A)-mediated metabolism and P-glycoprotein (P-gp)-mediated efflux, while flavonoids have been implicated as inhibitors of organic anion transporting polypeptide (OATP)-mediated absorptive uptake in the intestine. The potential for drug interactions with a food product necessitates an understanding of the expected concentrations of a suite of structurally diverse and potentially bioactive compounds.

Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma.

Romidepsin (Istodax), a selective inhibitor of histone deacetylases (HDACs), was approved for the treatment of cutaneous T-cell lymphoma in November 2009 by the US Food and Drug Administration. This unique natural product was discovered from cultures of Chromobacterium violaceum, a Gram-negative bacterium isolated from a Japanese soil sample. This bicyclic compound acts as a prodrug, its disulfide bridge being reduced by glutathione on uptake into the cell, allowing the free thiol groups to interact with Zn ions in the active site of class I and II HDAC enzymes.