The gut microbiota provides a wide range of beneficial functions for the host, and has an immense effect on the host's health status. The presence of microbiome in the gut may often influence the effect of an orally administered drug. Molecular mechanisms of this process are however mostly unclear. We investigated how the effect of a nonsteroidal drug nabumetone on expression of drug metabolizing enzymes (DMEs) in mice intestine and liver is changed by the presence of microbiota, here, using the germ free (GF) and specific pathogen free (SPF) BALB/c mice. First, we have found in a preliminary experiment that in the GF mice there is a tendency to increase bioavailability of the active form of nabumetone, which we have found now to be possibly influenced by differences in expression of DMEs in the GF and SPF mice. Indeed, we have observed that the expression of the most of selected cytochromes P450 (CYPs) was significantly changed in the small intestine of GF mice compared to the SPF ones. Moreover, orally administered nabumetone itself altered the expression of some CYPs and above all, in different ways in the GF and SPF mice. In the GF mice, the expression of the DMEs (CYP1A) responsible for the formation of active form of the drug are significantly increased in the small intestine and liver after nabumetone application. These results highlight the importance of gut microbiome in processes involved in drug metabolism in the both gastrointestinal tract and in the liver with possible clinical relevance.

• MeSH
• antiflogistika nesteroidní aplikace a dávkování   metabolismus   MeSH
• aplikace orální MeSH
• Bacteria metabolismus   MeSH
• cytochrom P-450 CYP1A1 metabolismus   MeSH
• dysbióza MeSH
• játra účinky léků   enzymologie   MeSH
• metabolická aktivace MeSH
• myši inbrední BALB C MeSH
• nabumeton aplikace a dávkování   metabolismus   MeSH
• střevní mikroflóra * MeSH
• systém (enzymů) cytochromů P-450 genetika   metabolismus   MeSH
• tenké střevo účinky léků   enzymologie   mikrobiologie   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• cytochrom P-450 CYP1A1 MeSH
• nabumeton MeSH
• systém (enzymů) cytochromů P-450 MeSH
• transkripční faktory MeSH

The efficacy of anthelmintic therapy of farm animals rapidly decreases due to drug resistance development in helminths. In resistant isolates, the increased expression and activity of drug-metabolizing enzymes (DMEs), e.g. cytochromes P450 (CYPs), UDP-glycosyltransferases (UGTs) and P-glycoprotein transporters (P-gps), in comparison to sensitive isolates have been described. However, the mechanisms and circumstances of DMEs induction are not well known. Therefore, the present study was designed to find the changes in expression of CYPs, UGTs and P-gps in adult parasitic nematodes Haemonchus contortus exposed to sub-lethal doses of the benzimidazole anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO). In addition, the effect of ABZ at sub-lethal doses on the ability to deactivate ABZ during consequent treatment was studied. The results showed that contact of H. contortus adults with sub-lethal doses of ABZ and ABZSO led to a significant induction of several DMEs, particularly cyp-2, cyp-3, cyp-6, cyp-7, cyp-8, UGT10B1, UGT24C1, UGT26A2, UGT365A1, UGT366C1, UGT368B2, UGT367A1, UGT371A1, UGT372A1 and pgp-3, pgp-9.1, pgp-9.2, pgp-10. This induction led to increased formation of ABZ metabolites (especially glycosides) and their increased export from the helminths' body into the medium. The present study demonstrates for the first time that contact of H. contortus with sub-lethal doses of ABZ (e.g. during underdose treatment) improves the ability of H. contortus adults to deactivate ABZ in consequent therapy.

• Klíčová slova
• ABC-transporters, P-glycoprotein, UDP-glycosyl transferases, anthelmintics, benzimidazoles, cytochromes P450, drug resistance, nematode,
• MeSH
• albendazol analogy a deriváty   farmakologie   MeSH
• antinematodní látky farmakologie   MeSH
• Haemonchus účinky léků   enzymologie   MeSH
• léková rezistence * MeSH
• metabolická inaktivace MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• albendazol MeSH
• albendazole sulfoxide MeSH Prohlížeč
• antinematodní látky MeSH

Prenylflavonoids in the human organism exhibit various health-beneficial activities, although they may interfere with drugs via the modulation of the expression and/or activity of drug-metabolizing enzymes. As intestinal cells are exposed to the highest concentrations of prenylflavonoids, we decided to study the cytotoxicity and modulatory effects of the four main hop-derived prenylflavonoids on the activities and mRNA expression of the main drug-conjugating enzymes in human CaCo-2 cells. Proliferating CaCo-2 cells were used for these purposes as a model of colorectal cancer cells, and differentiated CaCo-2 cells were used as an enterocyte-like model. All the tested prenylflavonoids inhibited the CaCo-2 cells proliferation, with xanthohumol proving the most effective (IC50 8.5 µM). The prenylflavonoids modulated the activities and expressions of the studied enzymes to a greater extent in the differentiated, as opposed to the proliferating, CaCo-2 cells. In the differentiated cells, all the prenylflavonoids caused a marked increase in glutathione S-transferase and catechol-O-methyltransferase activities, while the activity of sulfotransferase was significantly inhibited. Moreover, the prenylflavonoids upregulated the mRNA expression of uridine diphosphate (UDP)-glucuronosyl transferase 1A6 and downregulated that of glutathione S-transferase 1A1/2.

• Klíčová slova
• CaCo-2 cells, UDP-glucuronosyl transferase, catechol-O-methyltransferase, enzymatic activity, glutathione S-transferase, mRNA expression, prenylflavonoid, sulfotransferase, xanthohumol,
• MeSH
• buněčná diferenciace účinky léků   genetika   MeSH
• Caco-2 buňky MeSH
• exprese genu účinky léků   MeSH
• flavonoidy izolace a purifikace   farmakologie   MeSH
• glukuronosyltransferasa genetika   metabolismus   MeSH
• glutathiontransferasa genetika   metabolismus   MeSH
• Humulus chemie   MeSH
• katechol-O-methyltransferasa genetika   metabolismus   MeSH
• lidé MeSH
• neopren izolace a purifikace   farmakologie   MeSH
• proliferace buněk účinky léků   genetika   MeSH
• propiofenony izolace a purifikace   farmakologie   MeSH
• sulfotransferasy genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• flavonoidy MeSH
• glukuronosyltransferasa MeSH
• glutathiontransferasa MeSH
• GSTA1 protein, human MeSH Prohlížeč
• katechol-O-methyltransferasa MeSH
• neopren MeSH
• prenyl MeSH Prohlížeč
• propiofenony MeSH
• sulfotransferasy MeSH
• UDP-glucuronosyltransferase, UGT1A6 MeSH Prohlížeč
• xanthohumol MeSH Prohlížeč

Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, exerts many beneficial effects on human health such as antioxidant, anti-inflammatory, and anticancer effects. The effect of SFN alone on drug-metabolizing enzymes (DMEs) has been investigated in numerous in vitro and in vivo models, but little is known about the effect of SFN in combination with cytochrome P450 (CYP) inducer. The aim of our study was to evaluate the effect of SFN on the activity and gene expression of selected DMEs in primary cultures of rat hepatocytes treated or non-treated with β-naphthoflavone (BNF), the model CYP1A inducer. In our study, SFN alone did not significantly alter the activity and expression of the studied DMEs, except for the glutathione S-transferase (GSTA1) mRNA level, which was significantly enhanced. Co-treatment of hepatocytes with SFN and BNF led to a substantial increase in sulfotransferase, aldoketoreductase 1C, carbonylreductase 1 and NAD(P)H:quinone oxidoreductase 1 activity and a marked decrease in cytochrome P450 (CYP) Cyp1a1, Cyp2b and Cyp3a4 expression in comparison to the treatment with BNF alone. Sulforaphane is able to modulate the activity and/or expression of DMEs, thus shifting the balance of carcinogen metabolism toward deactivation, which could represent an important mechanism of its chemopreventive activity.

• Klíčová slova
• NAD(P)H:quinone oxidoreductase 1, cytochrome P450, drug-metabolizing enzymes, enzyme activity, gene expression, glutathione S-transferase, sulforaphane, β-naphthoflavone,
• MeSH
• beta-naftoflavon farmakologie   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• isothiokyanatany farmakologie   MeSH
• messenger RNA metabolismus   MeSH
• metabolická inaktivace MeSH
• potkani Wistar MeSH
• sulfoxidy MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• beta-naftoflavon MeSH
• isothiokyanatany MeSH
• messenger RNA MeSH
• sulforaphane MeSH Prohlížeč
• sulfoxidy MeSH