Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale)

Mei, Nan; Guo, Lei; Zhang, Lu; Shi, Leming; Sun, Yongming; Moland, Carrie L.; Dial, Stacey L.; Fuscoe, James C.; Chen, Tao

doi:10.1186/1471-2105-7-s2-s16

Cited by 33 publications

(43 citation statements)

References 56 publications

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“…21) Although KTE altered the mRNA levels of drug-metabolizing enzymes by 2-to 5-fold in our study, comfrey was found to change them by as much as 20-to 100-fold. 21,22) In this study, there were no significant differences in AST or ALT activities between the KTE-treated and the control mice. Furthermore, hepatoprotective and antioxidative effects have been reported for hot-water extracts of the roots and stems of KT in liver injury model mice.…”

Section: Discussionmentioning

confidence: 70%

“…[21][22][23][24] Using DNA microarray analysis, Mei et al founds that comfrey drastically regulates many CYP genes (e.g., CYP2A12, CYP4A12, CYP7A1, CYP2C12, and CYP26), GST genes (Gsta3, Gstm3, and Gstp1), ATP-binding cassette transporters (e.g., Abcb9 and Abcc3), and other metabolism-associated genes in the rat liver. 21) Although KTE altered the mRNA levels of drug-metabolizing enzymes by 2-to 5-fold in our study, comfrey was found to change them by as much as 20-to 100-fold. 21,22) In this study, there were no significant differences in AST or ALT activities between the KTE-treated and the control mice.…”

Section: Discussionmentioning

confidence: 99%

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Safety Evaluation of the Aqueous Extract Kothala Himbutu (Salacia reticulata) Stem in the Hepatic Gene Expression Profile of Normal Mice Using DNA Microarrays

Miyata

Nakatani

et al. 2008

Bioscience, Biotechnology, and Biochemistry

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Kothala himbutu is a traditional Ayurvedic medicinal plant used to treat diabetes. We aimed to evaluate the safety of an aqueous extract of Kothala himbutu stem (KTE) in normal mice. The mice were divided into two groups: one was administered KTE and the other distilled water for 3 weeks. During the test period, the groups showed no significant differences in body weight gain or plasma parameters, such as fasting blood glucose level, oral glucose tolerance test, or aspartate transaminase (AST) or alanine transaminase (ALT) activity. DNA microarray analysis revealed that expression of genes of known function, such as those for the stress response, ribosomal proteins, transcription, cell function, the inflammatory/immune response, and metabolism (xenobiotic, glutathione, etc.) remained largely unaffected by KTE. However some genes such as catechol-o-methyltransferase and succinyl-CoA synthetase were regulated by KTE, indicating that KTE is not toxic to normal mice and might be effective as a functional food.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Safety Evaluation of the Aqueous Extract Kothala Himbutu (Salacia reticulata) Stem in the Hepatic Gene Expression Profile of Normal Mice Using DNA Microarrays

Miyata

Nakatani

et al. 2008

Bioscience, Biotechnology, and Biochemistry

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“…However, comfrey is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Mei et al (36) studied the comfrey-induced gene expression profile of 26,857 genes in the livers of rats by DNA microarray analysis. Groups of 6 male transgenic Big Blue rats were fed a basal diet (control) or a diet containing 8% comfrey roots, a dose that resulted in liver tumors in a previous carcinogenicity bioassay, for 12 weeks and sacrificed one day after the final treatment.…”

Section: Pathway and Network Analysesmentioning

confidence: 99%

“…An excellent example is the mechanistic study of comfrey-induced hepatotoxicity and tumorigenicity (74). Comfrey contains several tumorigenic pyrrolizidine alkaloids, known to induce liver tumors in rats through a genotoxic mechanism (34, 36, 72). The expression profiles in the liver of Big Blue Fisher 344 rats treated with comfrey or riddelliine, a pyrrolizidine alkaloid, were analyzed and compared.…”

Section: Use Of Dna Microarray Analysis For Consequent Mechanism Detementioning

confidence: 99%

“…Our primary studies included the identification of toxic contaminants and tumorigenic components, determination of the mechanisms leading to hepatotoxicity and tumorigenicity in experimental animals, and DNA microarray study of gene expression profiles (12, 29–36). For example, we used DNA microarray technology to identify gene expression alterations induced by exposures of kava extract and GBE to rats and mice and elucidated their potential roles in liver toxicity (31–33).…”

Section: Introductionmentioning

confidence: 99%

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

Guo

Mei

Xia

et al. 2010

Journal of Environmental Science and Health, Part C

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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 toxic-ity 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.

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MicroRNAs and their predicted target messenger RNAs are deregulated by Exposure to a Carcinogenic Dose of Comfrey in Rat Liver

Fuscoe

Chen

2011

Environ and Mol Mutagen

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MicroRNAs (MiRNAs) are small noncoding RNAs that function as regulators of gene expression to control cell growth and differentiation. In this study, we analyzed miRNA and mRNA expression in the livers of rats treated with a carcinogenic dose of comfrey (Symphytum officinale) for 12 weeks. Groups of six rats were fed a normal diet or a diet containing 8% comfrey root. The animals were sacrificed 1 day after the last treatment and the livers were isolated for miRNA expression analysis using LC Sciences miRNA microarrays and for mRNA expression analysis using Affymetrix rat genome microarrays. MiRNA expression levels were significantly changed by comfrey treatment. The treated samples were separated clearly from the control samples in both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Quantitative measurements of seven miRNAs using TaqMan real-time PCR were consistent with the microarray results in terms of fold-change and the direction of the change in expression. Forty-five miRNAs (P < 0.01) and 1,921 mRNAs (q = 0) were significantly changed by comfrey treatment. Using a target prediction algorithm, 434 differentially expressed genes (DEGs) were predicted to be targeted by the differentially expressed miRNAs (DEMs). The DEM-targeted DEGs were more likely to be involved in carcinogenesis than the DEGs that were not targeted by the DEMs. The nontargeted DEGs were enriched in noncancer-related biological processes. Our data suggest that comfrey may exert its carcinogenic effects by disturbing miRNA expression resulting in altered mRNA levels of the DEM-targeted genes that are functionally associated with carcinogenesis.

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Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale)

Cited by 33 publications

References 56 publications

Safety Evaluation of the Aqueous Extract Kothala Himbutu (Salacia reticulata) Stem in the Hepatic Gene Expression Profile of Normal Mice Using DNA Microarrays

Safety Evaluation of the Aqueous Extract Kothala Himbutu (Salacia reticulata) Stem in the Hepatic Gene Expression Profile of Normal Mice Using DNA Microarrays

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

MicroRNAs and their predicted target messenger RNAs are deregulated by Exposure to a Carcinogenic Dose of Comfrey in Rat Liver

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