Teucrin A

Herbal bioactivation, molecular targets and the toxicity relevance.[Pubmed:21459083]

Chem Biol Interact. 2011 Jul 15;192(3):161-76.

There have been increasing reports on the adverse reactions associated with herbal consumption. For many of these adverse reactions, the underlying biochemical mechanisms are unknown, but bioactivation of herbal compounds to generate reactive intermediates have been implicated. This minireview updates our knowledge on metabolic activation of herbal compounds, molecular targets and the toxicity relevance. A number of studies have documented that some herbal compounds can be converted to toxic or even carcinogenic metabolites by Phase I [e.g. cytochrome P450s (CYPs)] and less frequently by Phase II enzymes. For example, 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 and myc oncogenes and gene mutation in renal cells and finally carcinogenesis of the kidneys. Teucrin A and teuchamaedryn A, two diterpenoids found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming herbal supplements that caused severe hepatotoxicity, are converted by CYP3A4 to reactive epoxide which reacts with proteins such as CYP3A and epoxide hydrolase and inactivate them. Some naturally occurring alkenylbenzenes (e.g. safrole, methyleugenol and estragole) and flavonoids (e.g. quercetin) can undergo bioactivation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts. Extensive pulegone metabolism generated p-cresol that is a glutathione depletory. The hepatotoxicity of kava is possibly due to intracellular glutathione depletion and/or quinone formation. Moreover, several herbal compounds including capsaicin from chili peppers, dially sulfone in garlic, methysticin and dihydromethysticin in kava, oleuropein in olive oil, and resveratrol found in grape seeds are mechanism-based (suicide) inhibitors of various CYPs. Together with advances of proteomics, metabolomics and toxicogenomics, an integrated systems toxicological approach may provide deep insights into mechanistic aspects of herb-induced toxicities, and contribute to bridging the relationships between herbal bioactivation, protein/DNA adduct formation and the toxicological consequences.

Identification of the protein targets of the reactive metabolite of teucrin A in vivo in the rat.[Pubmed:17892266]

Chem Res Toxicol. 2007 Oct;20(10):1393-408.

Covalent modification of proteins is associated with the toxicity of many electrophiles, and the identification of relevant in vivo protein targets is a desirable but challenging goal. Here, we describe a strategy for the enrichment of adducted proteins utilizing single-chain fragment variable (ScFv) antibodies selected using phage-display technology. Teucrin A is a furan-containing diterpenoid found in the herb germander that is primarily responsible for the herb's hepatotoxicity in rodents and humans following metabolic activation by cytochrome P450 enzymes. Conjugates of the 1,4-enedial derivative of Teucrin A, its presumed toxic metabolite, with lysine- and cysteine-containing peptides were synthesized and used to select ScFvs from a rodent phage-displayed library, which recognized the terpenoid moiety of the teucrin-derived adducts. Immunoaffinity isolation of adducted proteins from rat liver homogenates following administration of a toxic dose of Teucrin A afforded a family of proteins that were identified by liquid chromatography/tandem mass spectrometry. Of the 46 proteins identified in this study, most were of mitochondrial and endoplasmic reticulum origin. Several cytosolic proteins were found, as well as four peroxisomal and two secreted proteins. Using Ingenuity Pathway Analysis software, two significant networks involving the target genes were identified that had major functions in gene expression, small molecule biochemistry, and cellular function and maintenance. These included proteins involved in lipid, amino acid, and drug metabolism. This study illustrates the utility of chemically synthesized biological conjugates of reactive intermediates and the potential of the phage display technology for the generation of affinity reagents for the isolation of adducted proteins.

Two contemporary cases of hepatitis associated with Teucrium chamaedrys L. decoction use: case reports and review of literature.[Pubmed:21848806]

Basic Clin Pharmacol Toxicol. 2011 Dec;109(6):521-6.

Teucrium chamaedrys L. is a herbaceous plant common in European woods that has been used for many purposes for centuries. Recently, T. chamaedrys L. has become popular as a slimming decoction without any scientific proof of efficacy notwithstanding its well-known hepatotoxicity. Hydroalcoholic extracts are currently used as flavourings in the preparation of wines, bitters and liqueurs. Teucrin A and teuchamaedryn A are the major toxic components of the diterpenoid fraction of T. chamaedrys L.

Isolation and characterisation of selected germander diterpenoids from authenticated Teucrium chamaedrys and T. canadense by HPLC, HPLC-mS and NMR.[Pubmed:16910040]

Phytochem Anal. 2006 Jul-Aug;17(4):243-50.

Teucrium species, such as germander, are rich in neo-clerodane diterpenoids and have been used in traditional folk medicine for their stimulant, diuretic, antipyretic and antiseptic properties. However, the furano neo-clerodane diterpenoids present in germander have been implicated in the in vivo hepatotoxicity of this botanical. In this study, authenticated germander (Teucrium chamaedrys L. and Teucrium canadense L.) was used as the source material. Methanol extracts of powdered plant mate rial were prepared and analysed by HPLC using Synergi Max-RP columns with monitoring at 220 nm. Limited amounts of Teucrin A and other diterpenoid standards were analysed on a Synergi Max-RP column in order to determine their retention times and to generate calibration curves. The same standards were subjected to concurrent mass spectral analysis. Teucrin A and diterpenoids such as dihydroteugin, teuflin, teuflidin and teucvidin were tentatively identified in the plant extracts by HPLC-MS and 1H-NMR experiments. For the isolation of teucrium diterpenoids on a semipreparative scale, a solid-phase extraction method was developed for the first time using styrene divinylbenzene and strata-X sorbents for Teucrin A and teuflin, respectively. Semi-preparative HPLC of the methanol extract of the powdered aerial parts of Teucrium plants was carried out on a semipreparative Synergi Max-RP column with photodiode array detection in order to confirm the identities of some diterpenoids by HPLC-MS and NMR.