Unveiling the Impact of Morphine on Tamoxifen Metabolism in Mice in vivo

Background- Tamoxifen is used to treat breast cancer and cancer recurrences. After administration, tamoxifen is converted into two more potent antitumor compounds, 4OH-tamoxifen and endoxifen by the CYP3A4/5 and 2D6 enzymes in human. These active compounds are inactivated by the same UDP-glucuronosyltransferases isoforms as those involved in the metabolism of morphine. Importantly, cancer-associated pain can be treated with morphine, and the common metabolic pathway of morphine and tamoxifen suggests potential clinically relevant interactions. Methods- Mouse liver microsomes were used to determine the impact of morphine on 4OH-tamoxifen metabolism in vitro. For in vivo experiments, female mice were first injected with tamoxifen alone and then with tamoxifen and morphine. Blood was collected, and LC-MS/MS was used to quantify tamoxifen, 4OH-tamoxifen, N-desmethyltamoxifen, endoxifen, 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Results- In vitro, we found increased Km values for the production of 4OH-tamoxifen-glucuronide in the presence of morphine, suggesting an inhibitory effect on 4OH-tamoxifen glucuronidation. Conversely, in vivo morphine treatment decreased 4OH-tamoxifen levels in the blood while dramatically increasing the formation of inactive metabolites 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Conclusions- Our findings emphasize the need for caution when extrapolating results from in vitro metabolic assays to in vivo drug metabolism interactions. Importantly, morphine strongly impacts tamoxifen metabolism in mice. It suggests that tamoxifen efficiency could be reduced when both drugs are co-administered in a clinical setting, e.g. to relieve pain in breast cancer patients. Further studies are needed to assess the potential for tamoxifen-morphine metabolic interactions in humans

Subretinal electronic chips allow blind patients to read letters and combine them to words

A light-sensitive, externally powered microchip was surgically implanted subretinally near the macular region of volunteers blind from hereditary retinal dystrophy. The implant contains an array of 1500 active microphotodiodes (‘chip’), each with its own amplifier and local stimulation electrode. At the implant's tip, another array of 16 wire-connected electrodes allows light-independent direct stimulation and testing of the neuron–electrode interface. Visual scenes are projected naturally through the eye's lens onto the chip under the transparent retina. The chip generates a corresponding pattern of 38 × 40 pixels, each releasing light-intensity-dependent electric stimulation pulses. Subsequently, three previously blind persons could locate bright objects on a dark table, two of whom could discern grating patterns. One of these patients was able to correctly describe and name objects like a fork or knife on a table, geometric patterns, different kinds of fruit and discern shades of grey with only 15 per cent contrast. Without a training period, the regained visual functions enabled him to localize and approach persons in a room freely and to read large letters as complete words after several years of blindness. These results demonstrate for the first time that subretinal micro-electrode arrays with 1500 photodiodes can create detailed meaningful visual perception in previously blind individuals

Selenium biochemistry and its role for human health

Despite its very low level in humans, selenium plays an important and unique role among the (semi)metal trace essential elements because it is the only one for which incorporation into proteins is genetically encoded, as the constitutive part of the 21st amino acid, selenocysteine. Twenty-five selenoproteins have been identified so far in the human proteome. The biological functions of some of them are still unknown, whereas for others there is evidence for a role in antioxidant defence, redox state regulation and a wide variety of specific metabolic pathways. In relation to these functions, the selenoproteins emerged in recent years as possible biomarkers of several diseases such as diabetes and several forms of cancer. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important requisite to elucidate its preventing/therapeutic effect for human diseases. This review summarizes the most recent findings on the biochemistry of active selenium species in humans, and addresses the latest evidence on the link between selenium intake, selenoproteins functionality and beneficial health effects. Primary emphasis is given to the interpretation of biochemical mechanisms rather than epidemiological/observational data. In this context, the review includes the following sections: (1) brief introduction; (2) general nutritional aspects of selenium; (3) global view of selenium metabolic routes; (4) detailed characterization of all human selenoproteins; (5) detailed discussion of the relation between selenoproteins and a variety of human diseases

Étude du lien entre le dimorphisme sexuel observé dans le métabolisme et l’effet antinociceptif de la morphine

Morphine effects are influenced by sex. In rodents, morphine metabolism involves its glucuronidation to morphine-3-glucuronide (M3G). Interestingly, M3G has been shown to produce hyperalgesia. M3G pronociceptive effect could oppose morphine-induced antinociception. Morphine potency was higher in males than females and morphine antinociceptive tolerance developed earlier in females during the protocol. M3G pronociceptive effect did not seem to be influenced by sex. Morphine and M3G were quantified in the blood and some pain-related brain regions after morphine injection. The M3G/morphine metabolic ratios were dramatically higher in females than in males. In vivo central metabolism of morphine was observed. To conclude, peripheral and central metabolism of morphine are influenced by sex and central metabolism could participate in the sex differences observed in morphine antinociception. However, its implication seems limited during the induction of morphine antinociceptive tolerance.Les effets de la morphine sont influencés par le sexe. Chez le rongeur, son métabolisme implique sa glucuronidation en morphine-3-glucuronide (M3G). La M3G provoque une hyperalgésie qui pourrait s’opposer aux effets antinociceptifs de la morphine. Nous avons constaté que l’antinociception induite par la morphine est plus forte chez la souris mâle et que la tolérance antinociceptive se développe plus rapidement chez la souris femelle. La M3G possède un effet pronociceptif qui ne semble pas dépendre du sexe. Nous avons quantifié la morphine et la M3G dans le sang et dans des régions cérébrales impliquées dans le contrôle de la douleur après une injection de morphine, et nous avons constaté que les ratios métaboliques M3G/morphine étaient largement supérieurs chez les femelles. Nous avons également observé un métabolisme central de la morphine in vivo. Nous avons conclu que le métabolisme périphérique et central était influencé par le sexe et que le métabolisme central de la morphine pourrait participer aux différences d’antinociception liées au sexe. Cependant, son implication dans la tolérance antinociceptive semble limitée

Metabolism as a potential origin of sex differences in morphine-induced analgesia and tolerance

Les effets de la morphine sont influencés par le sexe. Chez le rongeur, son métabolisme implique sa glucuronidation en morphine-3-glucuronide (M3G). La M3G provoque une hyperalgésie qui pourrait s’opposer aux effets antinociceptifs de la morphine. Nous avons constaté que l’antinociception induite par la morphine est plus forte chez la souris mâle et que la tolérance antinociceptive se développe plus rapidement chez la souris femelle. La M3G possède un effet pronociceptif qui ne semble pas dépendre du sexe. Nous avons quantifié la morphine et la M3G dans le sang et dans des régions cérébrales impliquées dans le contrôle de la douleur après une injection de morphine, et nous avons constaté que les ratios métaboliques M3G/morphine étaient largement supérieurs chez les femelles. Nous avons également observé un métabolisme central de la morphine in vivo. Nous avons conclu que le métabolisme périphérique et central était influencé par le sexe et que le métabolisme central de la morphine pourrait participer aux différences d’antinociception liées au sexe. Cependant, son implication dans la tolérance antinociceptive semble limitée.Morphine effects are influenced by sex. In rodents, morphine metabolism involves its glucuronidation to morphine-3-glucuronide (M3G). Interestingly, M3G has been shown to produce hyperalgesia. M3G pronociceptive effect could oppose morphine-induced antinociception. Morphine potency was higher in males than females and morphine antinociceptive tolerance developed earlier in females during the protocol. M3G pronociceptive effect did not seem to be influenced by sex. Morphine and M3G were quantified in the blood and some pain-related brain regions after morphine injection. The M3G/morphine metabolic ratios were dramatically higher in females than in males. In vivo central metabolism of morphine was observed. To conclude, peripheral and central metabolism of morphine are influenced by sex and central metabolism could participate in the sex differences observed in morphine antinociception. However, its implication seems limited during the induction of morphine antinociceptive tolerance

Metabolism as a potential origin of sex differences in morphine-induced analgesia and tolerance

Les effets de la morphine sont influencés par le sexe. Chez le rongeur, son métabolisme implique sa glucuronidation en morphine-3-glucuronide (M3G). La M3G provoque une hyperalgésie qui pourrait s’opposer aux effets antinociceptifs de la morphine. Nous avons constaté que l’antinociception induite par la morphine est plus forte chez la souris mâle et que la tolérance antinociceptive se développe plus rapidement chez la souris femelle. La M3G possède un effet pronociceptif qui ne semble pas dépendre du sexe. Nous avons quantifié la morphine et la M3G dans le sang et dans des régions cérébrales impliquées dans le contrôle de la douleur après une injection de morphine, et nous avons constaté que les ratios métaboliques M3G/morphine étaient largement supérieurs chez les femelles. Nous avons également observé un métabolisme central de la morphine in vivo. Nous avons conclu que le métabolisme périphérique et central était influencé par le sexe et que le métabolisme central de la morphine pourrait participer aux différences d’antinociception liées au sexe. Cependant, son implication dans la tolérance antinociceptive semble limitée.Morphine effects are influenced by sex. In rodents, morphine metabolism involves its glucuronidation to morphine-3-glucuronide (M3G). Interestingly, M3G has been shown to produce hyperalgesia. M3G pronociceptive effect could oppose morphine-induced antinociception. Morphine potency was higher in males than females and morphine antinociceptive tolerance developed earlier in females during the protocol. M3G pronociceptive effect did not seem to be influenced by sex. Morphine and M3G were quantified in the blood and some pain-related brain regions after morphine injection. The M3G/morphine metabolic ratios were dramatically higher in females than in males. In vivo central metabolism of morphine was observed. To conclude, peripheral and central metabolism of morphine are influenced by sex and central metabolism could participate in the sex differences observed in morphine antinociception. However, its implication seems limited during the induction of morphine antinociceptive tolerance

Central metabolism as a potential origin of sex differences in morphine antinociception but not in the induction of antinociceptive tolerance in mice

International audienceBackground and Purpose-In rodents, morphine antinociception is influenced by sex. However, conflicting results have been reported regarding the interaction between sex and morphine antinociceptive tolerance. Morphine is metabolised in the liver and brain into morphine-3-glucuronide (M3G). Sex differences in morphine metabolism and differential metabolic adaptations during tolerance development might contribute to behavioural discrepancies. This article investigates the differences in peripheral and central morphine metabolism after acute and chronic morphine treatment in male and female mice. Experimental Approach-Sex differences in morphine antinociception and tolerance were assessed using the tail-immersion test. After acute and chronic morphine treatment, morphine and M3G metabolic kinetics in the blood were evaluated using LC-MS/MS. In addition, they were quantified in several central nervous system (CNS) regions. Finally, the blood-brain barrier (BBB) permeability of M3G was assessed in male and female mice. Key Results-This study demonstrated that female mice showed weaker morphine antinociception and faster induction of tolerance than males. Additionally, female mice showed higher levels of M3G in the blood and several pain-related CNS regions than male mice, whereas lower levels of morphine were observed in these regions. M3G brain/blood ratios after injection of M3G indicated no sex differences in M3G BBB permeability, and these ratios were lower than those obtained after injection of morphine. Conclusion-These differences are attributable mainly to morphine central metabolism, which differed between males and females in pain-related CNS regions, consistent with weaker morphine antinociceptive effects in females. However, the role of morphine metabolism in antinociceptive tolerance seemed limited

Schokolade - Nachhaltigkeit in einer globalen Wertschöpfungskette | FiBL Focus

Die Schweiz ist ein Schokoladenland und auch im Ausland für die gute Qualität der Schokoladenprodukte bekannt. Dabei wird Kakao in der Schweiz ja gar nicht angebaut. In der aktuellen Folge will Vanessa Gabel vom "FiBL Focus"-Podcast unter anderem auch auf die dunklere Schokoladenseite blicken und darüber sprechen, welche Schwierigkeiten es bei der Nachhaltigkeit in der Wertschöpfungskette für Schokolade noch gibt

Activity and molecular dynamics relationship within the family of human cholinesterase

The temperature dependence of the dynamics of recombinant human acetylcholinesterase (hAChE) and plasma human butyrylcholinesterase (hBChE) is examined using elastic incoherent neutron scattering. These two enzymes belong to the same family and present 50% amino acid sequence identity. However, significantly higher flexibility and catalytic activity of hAChE when compared to the ones of hBChE are measured. At the same time, the average height of the potential barrier to the motions is increased in the hBChE, e.g. more thermal energy is needed to cross it in the latter case, which might be the origin of the increase in activation energy and the reduction in the catalytic rate of hBChE observed experimentally. These results suggest that the motions on the picosecond timescale may act as a lubricant for those associated with activity occurring on a slower millisecond timescale