Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.

This review summarizes the importance of bile acids (BA) as important regulators of various homeostatic mechanisms with detailed focus on cytochrome P450 (CYP) enzymes. In the first part, synthesis, metabolism and circulation of BA is summarized and BA are reviewed as physiological ligands of nuclear receptors which regulate transcription of genes involved in their metabolism, transport and excretion. Notably, PXR, FXR and VDR are the most important nuclear receptors through which BA regulate transcription of CYP genes involved in the metabolism of both BA and xenobiotics. Therapeutic use of BA and their derivatives is also briefly reviewed. The physiological role of BA interaction with nuclear receptors is basically to decrease production of toxic non-polar BA and increase their metabolic turnover towards polar BA and thus decrease their toxicity. By this, the activity of some drug-metabolizing CYPs is also influenced what could have clinically relevant consequences in cholestatic diseases or during the treatment with BA or their derivatives.

SUMMARYWhat is known and Objective: Accurate prediction of actual CYP2D6 metabolic activity may prevent some adverse drug reactions and improve therapeutic response in patients receiving CYP2D6 substrates. Dextromethorphan-to-dextrorphan metabolic ratio (MR DEM WHAT IS KNOWN AND OBJECTIVECYP2D6 plays a pivotal role in the metabolism of many drugs. It is a highly polymorphic enzyme, and to date, more than 80 allelic variants alleles have been identified. 1 The variant alleles may encode proteins with normal (e.g. CYP2D6*2), decreased (e.g. CYP2D6*10) or no (e.g. CYP2D6*4) enzyme activity. As a consequence, there is a wide range of CYP2D6 metabolic activity shows wide inter-subject variability. The CYP2D6 metabolic phenotype can be classified into four groups -poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM). 2 Thus, the same dose of a drug extensively metabolized by CYP2D6 can result in a different clinical response in patients depending on the P450 phenotype. 2 Moreover, CYP2D6-drug interactions may also have clinical consequences. For example, after administration of paroxetine, a CYP2D6 inhibitor, to patients on tamoxifen, a decrease in plasma levels of the active metabolite of tamoxifen was detected. 3 This change may have serious consequences in breast cancer treatment with tamoxifen. CYP2D6 ultrarapid metabolizer phenotype may cause failure of pharmacotherapy because of the very low and thus ineffective drug plasma levels. 4 In antipsychotic treatment, an association has been observed between extrapyramidal adverse effects and the CYP2D6 genotype. 5 Therefore, for drugs with narrow therapeutic indices, it seems to be useful to assess CYP2D6 metabolic activity prior to or during therapy with CYP2D6 substrates and to adjust the individual dosage according to the patient's phenotype. Such personalized pharmacotherapy may prevent adverse effects and improve response. Specific substrates (markers) that are metabolized selectively by CYP2D6 are often used for the assessment of metabolic activity. The concentration of specific substrate and its metabolite in body fluids (a ratio of molar concentrations; metabolic ratio) serves as a measure of the individual CYP activity. Histograms of log-transformed metabolic ratios may show cut-off values of MR which distinguish EM from PM, UM or IM. Suitable substrates for CYP2D6 include debrisoquine, bufuralol, tramadol, dextromethorphan, metoprolol and sparteine. 2,6 Debrisoquine and sparteine are not currently available, and except for dextromethorphan, the other substrates are seldom administered. Dextromethorphan remains the most widely used probe for CYP2D6 metabolic activity

Totušek J., Tříska J., Lefnerová D., Strohalm J., Vrchotová N., Zendulka O., Průchová J., Chaloupková J., Novotná P., Houška M. (2011): Contents of sulforaphane and total isothiocyanates, antimutagenic activity, and inhibition of clastogenicity in pulp juices from cruciferous plants. Czech J. Food Sci., 29: 548-556.The consumption of Cruciferous vegetables is important for the prevention of cancerous diseases, particularly colorectal cancer. The effects of technological treatments (freezing, pasteurisation, high-pressure treatment) on the content of isothiocyanates, considered to be the active substance, were observed in single-species vegetable juices prepared from cruciferous vegetables (broccoli, cauliflower, Brussels sprouts, white and red cabbage). The contents of sulforaphane and total isothiocyanates were studied relative to the temperature, action period, and time delay after juice pressing. Sulforaphane and total isothiocyanates were determined by HPLC. Sulforaphane content in various parts of fresh broccoli was also assessed. Antimutagenic activity of the juices (frozen, pasteurised, and high-pressure treated) was evaluated using the Ames test and the following mutagens: AFTB1 (aflatoxin B1), IQ (2-amino-3-methyl-3H-imidazo-[4,5-f]quinoline), and MNU (2-nitroso-2-methylurea). Clastogenicity inhibition of the mutagens, in response to broccoli juice, as well as of pure sulforaphane, was observed using an in vivo experiment (the micronucleus test). It was shown that in terms of sulforaphane content, it is best to let broccoli juice stand for 60 min after pressing and pH adjustment. Sulforaphane content does not change under heating to 60°C. Its content decreases considerably (compared to fresh juice) with heating to higher temperatures than 60°C. High-pressure treatment preserves mutagenic inhibition to the same degree as juices freezing.

(-)-Linalool is the major floral scent occurring mainly in families Lamiaceae, Lauraceae and Rutaceae and is the main active compound of lavender oil. The purpose of this study was to reveal the influence of subchronic systemic treatment with (-)-linalool on the metabolic activity of CYP2A, 2B, 2C6, 2C11 and 3A in rat liver microsomes (RLM). The second aim was to reveal possible inhibitory effect of (-)-linalool on CYP2C6 in vitro. Wistar albino male rats were treated with (-)-linalool intragastrically at the doses of 40, 120, and 360 mg/kg/day for 13 days. Treatment with (-)-linalool at the dose of 360 mg/kg increased the metabolic activity of CYP2A assessed with testosterone as a probe substrate. (-)-Linalool showed weak competitive inhibition of CYP2C6 in rat liver microsomes, with IC50 of 84 μM with use of diclofenac as a probe substrate.