ABSTRACT
Botanical dietary supplements are complex mixtures with numerous potential sources of variation along the supply chain from raw plant material to the market. Approaches for determining sufficient similarity (ie, complex mixture read-across) may be required to extrapolate efficacy or safety data from a tested sample to other products containing the botanical ingredient(s) of interest. In this work, screening-level approaches for generating both chemical and biological-response profiles were used to evaluate the similarity of black cohosh (Actaea racemosa) and Echinacea purpurea samples to well-characterized National Toxicology Program (NTP) test articles. Data from nontargeted chemical analyses and gene expression of toxicologically important hepatic receptor pathways (aryl hydrocarbon receptor [AhR], constitutive androstane receptor [CAR], pregnane X receptor [PXR], farnesoid X receptor [FXR], and peroxisome proliferator-activated receptor alpha [PPARα]) in primary human hepatocyte cultures were used to determine similarity through hierarchical clustering. Although there were differences in chemical profiles across black cohosh samples, these differences were not reflected in the biological-response profiles. These findings highlight the complexity of biological-response dynamics that may not be reflected in chemical composition profiles. Thus, biological-response data could be used as the primary basis for determining similarity among black cohosh samples. Samples of E. purpurea displayed better correlation in similarity across chemical and biological-response measures. The general approaches described herein can be applied to complex mixtures with unidentified active constituents to determine when data from a tested mixture (eg, NTP test article) can be used for hazard identification of sufficiently similar mixtures, with the knowledge of toxicological targets informing assay selection when possible.
Subject(s)
Cimicifuga/chemistry , Dietary Supplements , Echinacea/chemistry , Gene Expression/drug effects , Hepatocytes/drug effects , Plant Preparations/chemistry , Plant Preparations/toxicity , Basic Helix-Loop-Helix Transcription Factors/genetics , Cells, Cultured , Constitutive Androstane Receptor , Hepatocytes/metabolism , Humans , PPAR alpha/genetics , Pregnane X Receptor/genetics , Primary Cell Culture , Receptors, Aryl Hydrocarbon/genetics , Receptors, Cytoplasmic and Nuclear/geneticsABSTRACT
OBJECTIVES: Impaired longitudinal growth and poor weight gain are common and important problems in children with cystic fibrosis. This study evaluates the hypothesis that adjunctive growth hormone (GH) therapy augments the growth response to nutritional supplementation. STUDY DESIGN: We recruited 18 prepubertal children who received enteral nutritional supplementation for at least 2 years before enrollment. Nine were randomly assigned to receive no GH for 1 year, followed by 1 year of GH. Nine were randomly assigned to receive 1 year of GH followed by a second year of GH. Measurements included height, weight, pulmonary function, lean tissue mass, bone mineral content, hospitalizations, outpatient antibiotic use, and caloric intake. RESULTS: Growth hormone resulted in significant improvement in height, weight, bone mineral content, lean tissue mass, and number of hospitalizations. Pulmonary function was similar at baseline. Absolute forced vital capacity and forced expiratory volume in 1 minute significantly increased in GH treatment, but there was no significant change in percent predicted pulmonary function. Caloric intake was similar in both groups during both years. CONCLUSIONS: These results suggest that GH is a useful for enhancing growth in children with cystic fibrosis receiving enteral nutritional supplementation.