Herbal Science Research - biotransformation

Biotransformation of Green Tea Polyphenols and the Biological Activities of Those Metabolites.

Site Editor — Fri, 02 Nov 2007 06:23:16 -0700

Biotransformation of Green Tea Polyphenols and the Biological Activities of Those Metabolites.: Mol Pharm. 2007 Oct 27; Authors: Lambert JD, Sang S, Yang CS

Green tea ( Camellia sinensis, Theaceae) and its major polyphenol constituents, the catechins, have been reported to have many health benefits including the prevention of cancer and heart disease. Many mechanisms of action have been proposed based on in vitro models; however, the importance of most of these mechanisms remains to be determined in vivo. The bioavailability and biotransformation of tea catechins play a key role in determining the importance of various mechanisms in vivo. Likewise, the biological activity and bioavailability of tea catechin metabolites, an understudied area, are important in understanding the potential beneficial effects of tea. In this article, we review the data available on the biotransformation of the tea catechins and the limited data set available on the biological activities of the catechin metabolites. Careful interpretation of available data, carefully designed animal experiments, and integration of bioavailability and biological activity data are needed if the disease preventive activity of tea is to be understood. We hope this article will spark research efforts on some of the important questions regarding tea polyphenol bioavailability, biotransformation, and the biological activities of tea catechin metabolites.

PMID: 17963356 [PubMed - as supplied by publisher]

Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update.

Site Editor — Thu, 04 Oct 2007 06:07:49 -0700

Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update.: Curr Drug Metab. 2007 Aug;8(6):526-53 Authors: Zhou SF, Xue CC, Yu XQ, Wang G

In recent years, there has been a globally increasing application of herbal medicines and dietary supplements to treat various chronic diseases and to promote health. However, there are increasing clinical reports on the organ toxicities associated with consumption of herbal medicines. This review updates the knowledge on metabolic activation of herbal components and its clinical and toxicological implications. Like many synthetic drugs undergoing metabolic activation to form reactive metabolites which are often associated with drug toxicity, it is recognized that some herbal components may also be converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450s (CYPs) and less frequently by Phase II conjugating enzymes. This is exemplified by aristolochic acids (AAs) in Aristolochia spp, which undergo reduction of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic tissues to generate highly reactive cyclic nitrenium ions. The latter can react with macromolecules (DNA and protein), resulting in activation of H-ras oncogene and gene mutation in renal cells and finally carcinogenesis of the kidneys. Some naturally occurring flavonoids (e.g. quercetin) and alkenylbenzenes (e.g. safrole, methyleugenol and estragole) can undergo metabolic activation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts and finally genotoxicity. Additional examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming dietary supplements but caused severe hepatotoxicity. Extensive pulegone metabolism generated p-cresol that was a glutathione depletory, whereas the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which can inactivate hepatic CYP3A and epoxide hydrolase through covalent binding. The hepatotoxic and carcinogenic species of plant pyrrolizidine alkaloids (e.g. echimidine and jacobine), namely pyrrole-type metabolites, are generated by hepatic CYP2B6 and CYP3A4. Potential mechanisms underlying the hepatotoxicity of kava have been related to intracellular glutathione depletion and/or quinone formation. Some herbal constituents (e.g. capsaicin from chili peppers, glabridin from licorice root, oleuropein in olive oil, dially sulfone in garlic, and resveratrol found in red wine) behave as mechanism-based inhibitors of various CYPs. This may provide an explanation for some reported herb-drug interactions. In addition, the inhibition of CYPs by herbal constituents may decrease the formation of toxic metabolites and thus inhibit carcinogenesis, as CYPs play an important role in procarcinogen activation. Due to the wide use and easy availability of herbal medicines, further research should be conducted to ensure the safety and quality of herbal medicine.

PMID: 17691916 [PubMed - indexed for MEDLINE]

The Induction of CYP1A2, CYP2D6 and CYP3A4 by Six Trade Herbal Products in Cultured Primary Human Hepatocytes.

Site Editor — Sat, 13 Jan 2007 21:34:04 -0800

The Induction of CYP1A2, CYP2D6 and CYP3A4 by Six Trade Herbal Products in Cultured Primary Human Hepatocytes.: Basic Clin Pharmacol Toxicol. 2007 Jan; 100(1): 23-30 Authors: Hellum BH, Hu Z, Nilsen OG

The aim of this study was to evaluate the in vitro inductive potential of six commonly used trade herbal products on CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Herbal components were extracted from the trade products in a way that ensured a composition equal to that present in the original product. Primary human hepatocytes and specific CYP substrates were used. Classic inducers were used as positive controls and herbal extracts were added in in vivo-relevant concentrations. Metabolites were determined by high performance liquid chromatography (HPLC). St. John's wort and common valerian were the strongest inducing herbs. In addition to induction of CYP3A4 by St. John's wort, common valerian and Ginkgo biloba increased the activity of CYP3A4 and 2D6 and CYP1A2 and 2D6, respectively. A general inhibitory potential was observed for horse chestnut, Echinacea purpurea and common sage. St. John's wort inhibited CYP3A4 metabolism at the highest applied concentration. Horse chestnut might be a herb with high inhibition potentials in vivo and should be explored further at lower concentrations. We show for the first time that G. biloba may exert opposite and biphasic effects on CYP1A2 and CYP2D6 metabolism. Induction of CYP1A2 and inhibition of CYP2D6 were found at low concentrations; the opposite was observed at high concentrations. CYP2D6 activity, regarded generally as non-inducible, was increased by exposure to common valerian (linear to dose) and G. biloba (highest concentration). An allosteric activation is suggested. From the data obtained, G. biloba, common valerian and St. John's wort are suggested as candidates for clinically significant CYP interactions in vivo.

Isolation and identification of phase II enzyme-inducing agents from nonpolar extracts of green onion (Allium spp.).

Site Editor — Sat, 06 Jan 2007 00:05:05 -0800

Isolation and identification of phase II enzyme-inducing agents from nonpolar extracts of green onion (Allium spp.).: J Agric Food Chem. 2006 Nov 1;54(22):8417-24 Authors: Xiao H, Parkin K

The objective of the study was to isolate and identify potential cancer preventive constituents from green onion based on the ability to induce quinone reductase (QR, a representative phase II enzyme) in murine hepatoma cells (Hepa 1c1c7). Crude nonpolar solvent extracts were prepared from freeze-dried green onion by sequential refluxing with hexane and then ethyl acetate, followed by liquid-liquid extraction. Active fractions were subjected to the Hepa 1c1c7 bioassay-guided steps of flash chromatography, thin layer chromatography (TLC), and high-pressure preparative liquid chromatography (HPLC) to afford pure isolates capable of inducing QR. Multiple fractions were active in inducing QR. Five pure compounds were isolated from active fractions and identified using spectroscopic methods; these were p-hydroxyphenethyl trans-ferulate (1), 5,6-dimethyl-2-pyridinecarboxylic acid (2), ferulic acid (3), 1-(6-hydroxy-[3]pyridyl)-propan-1-one (4), and N-trans-feruloyl 3-O-methyldopamine (5). p-Hydroxyphenethyl trans-ferulate (1) doubled QR specific activity in Hepa 1c1c7 cells at a level of 2.1 microg/mL (6.6 microM).

Echinacea purpurea supplementation stimulates select groups of human gastrointestinal tract microbiota.

Site Editor — Wed, 03 Jan 2007 19:02:30 -0800

Echinacea purpurea supplementation stimulates select groups of human gastrointestinal tract microbiota.: J Clin Pharm Ther. 2006 Dec;31(6):599-604 Authors: Hill LL, Foote JC, Erickson BD, Cerniglia CE, Denny GS

Background and objective: The objective of this research was to determine the effects of the dietary supplement Echinacea purpurea on aerobic and anaerobic bacteria common to the human gastrointestinal (GI) tract. Botanical extracts have shown in vitro antimicrobial effects against certain pathogenic bacteria. It is uncertain if medicinal herbs have any effect against pathogenic bacteria or on the native GI microbiota. Methods: Fifteen human subjects consumed 1000 mg of standardized E. purpurea for 10 days. Faecal samples were collected at baseline, 10 days and 17-18 days following supplementation. Samples were tested for select aerobic and anaerobic bacteria using plate culture microbiological methods. Results and discussion: Significant increases were found for total aerobic bacteria, Bacteroides group and Bacteroides fragilis after E. purpurea exposure. Supplementation did not significantly alter the number of enteric bacteria, enterococci, lactobacilli, bifidobacteria or total anaerobic bacteria. Conclusion: Echinacea supplementation has altered the GI microbiota. The health consequences associated with this change are unknown but previous research has shown increased Bacteroides concentrations associated with diarrhoea, inflammatory bowel disease and increased risk of colon cancer. Additional research should delineate the role of Echinacea in the stimulation of Bacteroides and describe the effects of other botanical supplements to the GI microbiota.

Plant extracts affect in vitro rumen microbial fermentation.

Site Editor — Fri, 09 Jun 2006 04:24:47 -0700

Plant extracts affect in vitro rumen microbial fermentation.: J Dairy Sci. 2006 Feb;89(2):761-71 Authors: Busquet M, Calsamiglia S, Ferret A, Kamel C

Different doses of 12 plant extracts and 6 secondary plant metabolites were incubated for 24 h in diluted ruminal fluid with a 50:50 forage:concentrate diet. Treatments were: control (no additive), plant extracts (anise oil, cade oil, capsicum oil, cinnamon oil, clove bud oil, dill oil, fenugreek, garlic oil, ginger oil, oregano oil, tea tree oil, and yucca), and secondary plant metabolites (anethol, benzyl salicylate, carvacrol, carvone, cinnamaldehyde, and eugenol). Each treatment was supplied at 3, 30, 300, and 3,000 mg/L of culture fluid. At 3,000 mg/L, most treatments decreased total volatile fatty acid concentration, but cade oil, capsicum oil, dill oil, fenugreek, ginger oil, and yucca had no effect. Different doses of anethol, anise oil, carvone, and tea tree oil decreased the proportion of acetate and propionate, which suggests that these compounds may not be nutritionally beneficial to dairy cattle. Garlic oil (300 and 3,000 mg/L) and benzyl salicylate (300 and 3,000 mg/L) reduced acetate and increased propionate and butyrate proportions, suggesting that methane production was inhibited. At 3,000 mg/L, capsicum oil, carvacrol, carvone, cinnamaldehyde, cinnamon oil, clove bud oil, eugenol, fenugreek, and oregano oil resulted in a 30 to 50% reduction in ammonia N concentration. Careful selection and combination of these extracts may allow the manipulation of rumen microbial fermentation.

In vitro and in vivo assessment of herb drug interactions.

Site Editor — Fri, 09 Jun 2006 04:23:18 -0700

In vitro and in vivo assessment of herb drug interactions.: Life Sci. 2006 Jan 18; Authors: Venkataramanan R, Komoroski B, Strom S

Herbal products contain several chemicals that are metabolized by phase 1 and phase 2 pathways and also serve as substrates for certain transporters. Due to their interaction with these enzymes and transporters there is a potential for alteration in the activity of drug metabolizing enzymes and transporters in presence of herbal components. Induction and inhibition of drug metabolizing enzymes and transporters by herbal component has been documented in several in vitro studies. While these studies offer a system to determine the potential for a herbal component to alter the pharmacokinetics of a drug, they cannot always be used to predict the magnitude of any potential effect in vivo. In vivo studies are the ultimate way to determine the clinical importance of herb drug interactions. However, lack of content uniformity and lack of documentation of the bioavailability of herbal components makes even in vivo human studies difficult to interpret as the effect may be product specific. It appears that St. John's wort extract is probably one of the most important herbal product that increases the metabolism and decreases the efficacy of several drugs. Milk thistle on the other hand appears to have minimal effect on phase 1 pathways and limited data exists for phase 2 pathways and transporter activity in vivo. Further systematic studies are necessary to assess the significance of herb drug interactions.

[Effect of intestinal cytochrome P450 3A on phytochemical presystemic metabolism.]

Site Editor — Fri, 09 Jun 2006 04:21:09 -0700

[Effect of intestinal cytochrome P450 3A on phytochemical presystemic metabolism.]: Chin J Integr Med. 2005 Sep;11(3):232-6 Authors: Xia F, Chen XY

Phytochemicals, orally administered substances, are found to undergo presystemic metabolism mainly in the intestine. Although early researches confirmed the role of intestinal bacteria in phytochemical presystemic metabolism, along with the development of molecular biology in investigating intestinal metabolism, a breakthrough has been won in research into metabolizing enzymes and transporters in intestine, which demands more attention and further studies. Recently, Cytochrome P450 3A has been found to be the most effective enzyme in mediating both oxidative (PhaseI) and conjugative (PhaseII) metabolism in the intestine. The present review summarizes the current findings correlated with the effect of intestinal cytochrome P450 3A on phytochemical presystemic metabolism, which provides a good basis for further research on phytochemical pharmacokinetics.

High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart.

Site Editor — Fri, 09 Jun 2006 04:15:29 -0700

High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart.: Br J Nutr. 2005 Dec;94(6):873-6 Authors: Frankenfeld CL, Atkinson C, Thomas WK, Gonzalez A, Jokela T, Wähälä K, Schwartz SM, Li SS, Lampe JW

Particular intestinal bacteria are capable of metabolizing the soya isoflavone daidzein to equol and/or O-desmethylangolensin (O-DMA), and the presence of these metabolites in urine after soya consumption are markers of particular intestinal bacteria profiles. Prevalences of equol producers and O-DMA producers are approximately 30-50 % and 80-90 %, respectively, and limited observations have suggested that these daidzein-metabolizing phenotypes are stable within individuals over time. Characterizing stability of these phenotypes is important to understand their potential as markers of long-term exposure to particular intestinal bacteria and their associations with disease risk. We evaluated concordance within an individual for the equol-producer and O-DMA-producer phenotypes measured at two time points (T1, T2), 1-3 years apart. Phenotypes were ascertained by analysing equol and O-DMA using GC-MS in a spot urine sample collected after 3 d soya (source of daidzein) supplementation. In ninety-two individuals without recent (within 3 months before phenotyping) or current antibiotics use, 41 % were equol producers at T1 and 45 % were equol producers at T2, and 90 % were O-DMA producers at T1 and 95 % were O-DMA producers at T2. The percentage agreement for the equol-producer phenotype was 82 and for the O-DMA-producer phenotype was 89. These results indicate that these phenotypes are stable in most individuals over time, suggesting that they provide a useful biomarker for evaluating disease risk associated with harbouring particular intestinal bacteria responsible for, or associated with, the metabolism of the soya isoflavone daidzein.