Gene Expression Profiling as an Initial Approach for Mechanistic Studies of Toxicity and Tumorigenicity of Herbal Plants and Herbal Dietary Supplements

Abstract

Dietary supplements are consumed by more than 300 million people worldwide, and herbal dietary supplements represent the most rapidly growing portion of this industry. Even though adverse health effects of many herbal dietary supplements have been reported, safety assurances are not being addressed adequately. Toxicological data on the identification of genotoxic and tumorigenic ingredients in many raw herbs are also lacking. Currently, more than 30 herbal dietary supplements and active ingredients have been selected by the National Toxicology Program (NTP) for toxicity and tumorigenicity studies. Due to the complexity of the chemical components present in plant extracts, there are no established methodologies for determining the mechanisms of toxicity (particularly tumorigenicity) induced by herbs, such as Gingko biloba leaf extract (GBE) and other herbal plant extracts. Consequently, the understanding of toxicity of herbal dietary supplements remains limited.

We have proposed that application of DNA microarrays could be a highly practical initial approach for revealing biological pathways and networks associated with toxicity induced by herbal dietary supplements and the generation of hypotheses to address likely mechanisms. The changes in expression of subsets of genes of interest, such as the modulation of drug metabolizing genes, can be analyzed after treatment with an herbal dietary supplement. Although levels of gene expression do not represent fully the levels of protein activities, we propose that subsequent biochemical and genomic experiments based on these initial observations will enable elucidation of the mechanisms leading to toxicity, including tumorigenicity. This review summarizes the current practices of microarray analysis of gene expressions in animals treated with herbal dietary supplements and discusses perspectives for the proposed strategy.

Keywords:

• herbal dietary supplements
• DNA microarray
• drug metabolizing enzyme
• drug metabolizing gene
• gene expression
• toxicity
• tumorigenicity

ACKNOWLEDGMENTS

We thank Drs. James C. Fuscoe, Qiang Shi, and Frederick A. Beland from NCTR and Richard D. Irwin and Michael L. Cunningham from NIEHS for their critical review of this manuscript. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.

This article is not subject to US Copyright Laws.

The contents of this article do not necessarily reflect the views and policies of the U.S. Food and Drug Administration or the National Toxicology Program. The mention of trade names or commercial products does not constitute endorsement or recommendation for use.

Notes

^¶The data were from Guo et al. (31).

∗All changes are greater than 1.5 (up and down) with a P-value less than 0.05 compared to the controls and the symbol of minus (−) indicates down-regulation.

^¶The data were from Guo et al. (32).

∗All changes are greater than 2.0 (up and down) with a P-value less than 0.01compared to the controls and the symbol of minus (−) indicates down-regulation.

^¶The data were from Mei et al. (36).

∗All changes are greater than 2.0 (up and down) with a P-value less than 0.01compared to the controls and the symbol of minus (−) indicates down-regulation.

^¶The data were from Guo et al. (74).

∗All changes are greater than 2.0 (up and down) with a P-value less than 0.01compared to the controls and the symbol of minus (−) indicates down-regulation.