Chronic administration of tamoxifen to female rats causes hepatocellular carcinomas. We have investigated damage to liver DNA caused by the administration of tamoxifen to female Fischer F344/N rats or C57B1/6 or DBA/2 mice using 32P-postlabelling. Following the administration of tamoxifen for 7 days (45 mg/kg/day) and extraction of hepatic DNA, up to 7 radiolabelled adduct spots could be detected after PEI-cellulose chromatography of the 32P-labelled DNA digests. Tamoxifen caused a time-dependent increase in the level of adduct detected up to a value of at least 1 adduct/10(6) nucleotides after 7 days dosing. A dose response relationship was demonstrated over the range of 5-45 mg/kg/day (0.013-0.12 mmol/kg/day). On cessation of dosing there was a loss of adducts from the liver DNA. These adducts were not detected in DNA from vehicle-dosed controls or in DNA from kidney, lung, spleen, uterus or peripheral lymphocytes. Pyrrolidinotamoxifen caused a similar level of adduct formation as tamoxifen. In contrast, no significant adduct formation could be detected in liver DNA from rats given droloxifene or toremifene. Mice given tamoxifen (45 mg/kg/day for 4 days) showed levels of adducts in the liver which were 30-40% of those present in rats. Exposure of rat hepatocytes to tamoxifen in vitro, resulted in induction of unscheduled DNA synthesis, when preparations from rats which had been pretreated with tamoxifen in vivo were used. No such increase could be detected in hepatocytes from control rats, suggesting tamoxifen may induce enzymes responsible for its own activation. Tamoxifen induced a significant increase in micronucleus formation in a dose dependent manner in cultures of MCL-5 cells, a human cell line that expresses 5 different human cytochrome P450 isoenzymes, as well as epoxide hydrolase.
Over the last few years, the efforts to reveal through neuroscientific lens the relations between the mind, body, and built environment have set a promising direction of using neuroscience for architecture. However, little has been achieved thus far in developing a systematic account that could be employed for interpreting current results and providing a consistent framework for subsequent scientific experimentation. In this context, the enactive perspective is proposed as a guide to studying architectural experience for two key reasons. Firstly, the enactive approach is specifically selected for its capacity to account for the profound connectedness of the organism and the world in an active and dynamic relationship, which is primarily shaped by the features of the body. Thus, particular emphasis is placed on the issues of embodiment and motivational factors as underlying constituents of the body-architecture interactions. Moreover, enactive understanding of the relational coupling between body schema and affordances of architectural spaces singles out the two-way bodily communication between architecture and its inhabitants, which can be also explored in immersive virtual reality settings. Secondly, enactivism has a strong foothold in phenomenological thinking that corresponds to the existing phenomenological discourse in architectural theory and qualitative design approaches. In this way, the enactive approach acknowledges the available common ground between neuroscience and architecture and thus allows a more accurate definition of investigative goals. Accordingly, the outlined model of architectural subject in enactive terms—that is, a model of a human being as embodied, enactive, and situated agent, is proposed as a basis of neuroscientific and phenomenological interpretation of architectural experience.
Nowadays there is the hope that neuroscientific findings will contribute to the improvement of building design in order to create environments which satisfy man's demands. This can be achieved through the understanding of neurophysiological correlates of architectural perception. To this aim, the electroencephalographic (EEG) signals of 12 healthy subjects were recorded during the perception of three immersive virtual reality environments (VEs). Afterwards, participants were asked to describe their experience in terms of Familiarity, Novelty, Comfort, Pleasantness, Arousal, and Presence using a rating scale from 1 to 9. These perceptual dimensions are hypothesized to influence the pattern of cerebral spectral activity, while Presence is used to assess the realism of the virtual stimulation. Hence, the collected scores were used to analyze the Power Spectral Density (PSD) of the EEG for each behavioral dimension in the theta, alpha and mu bands by means of time-frequency analysis and topographic statistical maps. Analysis of Presence resulted in the activation of the frontal-midline theta, indicating the involvement of sensorimotor integration mechanisms when subjects expressed to feel more present in the VEs. Similar patterns also characterized the experience of familiar and comfortable VEs. In addition, pleasant VEs increased the theta power across visuomotor circuits and activated the alpha band in areas devoted to visuospatial exploration and processing of categorical spatial relations. Finally, the de-synchronization of the mu rhythm described the perception of pleasant and comfortable VEs, showing the involvement of left motor areas and embodied mechanisms for environment appreciation. Overall, these results show the possibility to measure EEG correlates of architectural perception involving the cerebral circuits of sensorimotor integration, spatial navigation, and embodiment. These observations can help testing architectural hypotheses in order to design environments matching the changing needs of humans.
The metabolisms of tamoxifen in female rat, mouse and human liver microsomal preparations were compared. Rat, mouse and human liver microsomes were incubated with tamoxifen in the presence of NADPH and MgCl2 and the metabolites formed were analysed by on-line HPLC-electrospray ionization MS. The major metabolites formed by rat liver microsomes were 4-hydroxytamoxifen, 4'-hydroxytamoxifen, N-desmethyltamoxifen and tamoxifen N-oxide. In addition, two epoxide metabolites, 3,4-epoxytamoxifen and 3',4'-epoxytamoxifen, and their hydrolysed derivatives, 3,4-dihydrodihydroxytamoxifen and 3',4'-dihydrodihydroxytamoxifen, have been identified. The pattern of the main metabolites obtained with human liver microsomes resembles qualitatively that of rat liver microsomes. The major differences between rat and human liver microsomes were that the amount of hydroxylated metabolites were much lower in human and only traces of 3,4-epoxytamoxifen and the corresponding dihydrodihydroxy derivative were detected. No 3',4'-epoxytamoxifen was detected in human liver microsomes. The four major metabolites were also formed in much larger amounts and with faster rates of formation by mouse liver microsomes, though tamoxifen N-oxide clearly predominated in this species. Polar metabolites, 3,4-dihydroxytamoxifen and 4-hydroxytamoxifen N-oxide, which were undetectable in rat and human, were formed in significant amounts in mouse microsomes. As in human microsomes, there was only one epoxide metabolite, 3,4-epoxytamoxifen, produced by mouse liver microsomes at levels lower than that found in rat. The faster rate of metabolism and the production of polar metabolites may indicate the ability of mouse to detoxify tamoxifen by rapid elimination compared with rat and human. The production of a larger amount of potentially reactive epoxide metabolites in rat may be responsible for the liver carcinogenesis in this species.
A green porphyrin-like pigment with inhibitory properties towards protohaem ferro-lyase activity was isolated from the livers of mice and rats after treatment with 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Mice, which are more sensitive to the porphyrogenic properties of the drug, produce more inhibitor. The non-porphyrogenic analogue 3,5-diethoxycarbonylcollidine does not cause accumulation of the pigment in the liver. The inhibitory substance is present in control liver at low but measurable concentrations.
1. The effect of a single dose of 2-allyl-2-isopropylacetamide on the cytochrome P-450 concentration in rat liver microsomal fraction was studied. The drug caused a rapid loss of cytochrome P-450 followed by a gradual increase to above the normal concentration. 2. The loss of cytochrome P-450 was accompanied by a loss of microsomal haem and by a brown-green discoloration of the microsomal fraction suggesting that a change in the chemical constitution of the lost haem had taken place. Direct evidence for this was obtained by prelabelling the liver haems with radioactive 5-aminolaevulate: the drug caused a loss of radioactivity from the haem with an increase of radioactivity in a fraction containing certain unidentified green pigments. 3. Evidence was obtained by a dual-isotopic procedure that rapidly turning-over haem(s) may be preferentially affected. 4. The loss of cytochrome P-450 as well as the loss of microsomal haem and the discoloration of the microsomal fraction were more intense in animals pretreated with phenobarbitone and were much less evident when compound SKF 525-A (2-diethylaminoethyl 3,3-diphenylpropylacetate) was given before 2-allyl-2-isopropylacetamide, suggesting that the activity of the drug-metabolizing enzymes may be involved in these effects. 5. The relevance of the destruction of liver haem to the increased activity of 5-aminolaevulate synthetase caused by 2-allyl-2-isopropylacetamide is discussed.Several chemically unrelated lipid-soluble drugs stimulate the hepatic formation of porphyrins in the experimental animal and in liver cells cultured in vitro (De Matteis, 1967, 1971, and in both systems enhance the activity of 5-aminolaevulate synthetase, the rate-limiting enzyme in the biosynthetic pathway of porphyrins and haem (Granick & Urata, 1963;Granick, 1966). This is thought to result from an interference by the drugs with the feedback control exercised by haem at the level of the enzyme (Granick, 1966), although the exact mechanism of this effect is not known.It has been reported (De Matteis, 1970) that one of these drugs, 2-allyl-2-isopropylacetamide, causes a rapid loss of cytochrome P-450 and haem from rat liver microsomal fraction coincidental with the rise in activity of 5-aminolaevulate synthetase. Preliminary evidence has also been presented indicating that the lost haem undergoes a change in chemical constitution, probably to certain illdefined green pigments (referred to below as 'green pigments') already described in the liver of animals with experimental porphyria (Schwartz & Ikeda, 1955).The present paper provides further information on the destruction of liver haem caused by 2-allyl-2-isopropylacetamide. The significance of this loss of haem in relation to the induction of 5-aminolaevulate synthetase caused by the drug is discussed. MATERIALS AND METHODSTreatment of animals. Male albino rats (150-180g) of the Porton strain were kept in experimental cages that had been designed to prevent coprophagy. They were starved for 24h before being injected with 2-allyl-2-isopropyla...
N-Methyl mesoporphyrin was a powerful inhibitor of protohaem ferro-lyase in vitro, whereas N-ethyl mesoporphyrin and N-methyl coproporphyrin were not and neither was the newly described green pigment produced by giving rats ethylene. This suggests that the size of the substituent at a pyrrole nitrogen and also the number of carboxylic acid side chains of the substituted porphyrin are important for the inhibitory effect. Evidence that N-methyl mesoporphyrin inhibited the enzyme, whereas the ethylene-derived pigment did not, was also obtained in vivo.
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