Biomedical subjects

G M Morris

Publications and source records attributed to G M Morris.

At least 55 records · Page 3Linked to original sources

PubMed1996

Images of cone photoreceptors in the living human eye.

Though the photoreceptor mosaic has been imaged through the intact optics of the eyes of several species, it has not been clear whether individual photoreceptors can be resolved in the living human eye. We have constructed a high-resolution fundus camera and have resolved cones with a spacing as small as 3.5 microns in single images of the fundus. The high contrast of these images implies that almost all the light returning from the retina at this wavelength (555 nm) has passed through the apertures of foveal cones. The average power spectra of our retinal images show that it is possible to recover spatial frequencies as high as 150 c/deg in eyes with normal optical quality, a conclusion that was confirmed with estimates of the optical quality of these eyes obtained with a Hartmann-Shack wavefront sensor. These results emphasize the superiority of the eye's optics over the spatial sampling limits of the retina when the eye's optical quality is optimized. They also show that it would be possible to routinely resolve retinal structures as small as photoreceptors in the normal living eye if its aberrations could be corrected.

Adult↗

PubMed1996

Boron neutron capture irradiation of the rat spinal cord: effects of variable doses of borocaptate sodium.

The Fischer 344 rat spinal cord model has been used to evaluate the response of the central nervous system to boron neutron capture irradiation with variable doses of the neutron capture agent, borocaptate sodium (BSH). Three doses of BSH, 190, 140 and 80 mg/kg body weight, administered by i.p. injection, were used to establish the time course of 10B accumulation in and removal from the blood. After administration of the two lower doses of BSH, blood 10B levels peaked at 0.5 h after injection, with no significant (P > 0.1) change at 1 h after injection. Beyond this time point, levels of 10B in the blood began to decrease after a dose of 80 mg/kg BSH, but remained constant until 3 h after administration after the two higher doses of BSH. Myelopathy developed after latent intervals of 20.4 +/- 0.1, 20.8 +/- 1.4, 15.0 +/- 0.8, 15.4 +/- 0.4 and 15.6 +/- 0.4 weeks, following irradiation with thermal neutrons in combination with BSH at doses of 20, 40, 80, 140 and 190 mg/kg body weight, respectively. The radiation-induced lesion in the spinal cord was white matter necrosis. ED50 values for myelopathy were calculated from probit-fitted dose-effect curves. Expressed as total physical absorbed doses, these values were 20.7 +/- 1.9, 24.9 +/- 1.2, 27.2 +/- 0.9, 28.4 +/- 0.6 and 32.4 +/- 1.9 Gy after irradiation with thermal neutrons in the presence of 20, 40, 80, 140 and 190 mg/kg body weight of BSH, respectively. The compound biological effectiveness (CBE) factor values, estimated from this data, were in the range 0.49-0.55. There was no significant (P > 0.1) variation in the CBE factor for BSH as a function of increasing 10B concentration in the blood. It was concluded that there was no significant synergistic interaction between the low and high linear energy transfer (LET) components of the boron neutron capture (BNC) radiation field.

Animals↗

PubMed1996

Review article: effects of radiation on the cell proliferation kinetics of epithelial tissues--therapeutic implications.

The cell kinetic responses of the epithelia of the skin, oral mucosa and intestine to photon irradiation are reviewed. One of the fundamental assumptions made in the development of mathematical models, used to predict the acute response of normal tissues to changes in fractionation protocols, is "equal effect per fraction". There is now accumulating cell kinetic data to indicate that this assumption is unlikely to be valid. The implications of these findings are discussed.

Animals↗

PubMed1996

Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascular-mediated pathogenesis.

A histopathological study was carried out on the spinal cord of rats after boron neutron capture (BNC) irradiation. Rats were irradiated with thermal neutrons alone or in combination with borocaptate sodium (BSH) or p-boronophenylalanine (BPA). Spinal cords were examined 1 year after irradiation, or at earlier times in rats developing myelopathy. Considered overall, the pathology of the spinal cord after BNC irradiation was comparable with that reported previously after X irradiation of the spinal cord in the identical strain of rat. When BSH was used as the neutron capture agent, the biologically effective dose of radiation delivered to the CNS parenchyma was a factor of -2.7 lower than that delivered to the vascular endothelium. In effect, the blood vessels were selectively irradiated using this BNC modality. The resultant pathology was similar to that observed after irradiation with thermal neutrons alone or in the presence of BPA, situations in which the CNS vasculature was not selectively irradiated. This points to the vascular endothelium as being the critical target cell population, damage to which results in the development of the lesions seen in the spinal cord after BNC irradiation and, by inference, after irradiation with more conventional modalities.

Alpha Particles↗

PubMed1995

Trophic effects of essential fatty acids on pig skin.

The daily oral administration of 3 ml of two oils (So-5407 and So-1129) containing essential fatty acids (EFAs) for 16 weeks resulted in a transient increase in cell proliferative activity in the skin of female Large White pigs. The So-5407 oil contained 7% gamma-linolenic acid (GLA) whereas So-1129 was an oil of similar composition, but with no GLA. Hyperplasia of the epidermis was observed after the administration of both oils, and this was characterized by an increase in the size of the rete pegs. The maximum effect occurred at 4 weeks after the start of oil administration, at which time the number of viable cell layers had increased by a factor of approximately 1.5, and mean epidermal thickness (excluding the stratum corneum) was approximately 40% greater than that of the epidermis prior to oil administration. There was a marked increase in the labelling index (LI) of the basal cell layer of the epidermis in pigs receiving So-5407. Maximum LIs were quantified at 4 weeks after the start of administration and were 18.8 +/- 1.3% and 13.1 +/- 1.7% for pigs receiving So-5407 and So-1129, respectively. After this time the LI declined progressively and had returned to values within normal limits (P > 0.1) by 8 weeks after the start of administration of both oils. A similar pattern of change in the LI was seen in the follicular epithelium, although the peak values at 4 weeks after the start of oil administration of 12.2 +/- 1.8% and 10.8 +/- 0.9 for the groups receiving So-5407 and So-1129, respectively, were lower than in the epidermis. Labelled cells were also counted in the papillary dermis and maximum values were again seen at 4 weeks after the start of oil administration. Of the two oils, So-1129 had the greatest effect, with the number of labelled cells in the papillary dermis being a factor of three to four-fold higher than in skin prior to oil administration, between 2 and 12 weeks after the start of administration.

Animals↗

PubMed1995

A comparison of the effects of methotrexate and misonidazole on the germinal cells of the subependymal plate of the rat.

The cytotoxic effects of the drugs methotrexate (MTX) and misonidazole have been assessed in the rat brain by quantifying changes in the constituent cell populations of a glial cell progenitor layer, the subependymal plate (SEP). Three distinct cell types can be identified in the SEP on the basis of their nuclear morphology: cells with small dark (SD), small light (SL) or large light (LL) nuclei. The cells with SD nuclei may present pluripotential glial cell precursors. A reduction in the total nuclear density of the SEP, after the local ventricular administration of MTX, could be accounted for largely by a loss of cells with SD nuclei; to approximately 45% of control values 2 days after MTX followed by a full recovery in numbers by day 5. A further decline in the number of cells with SD nuclei occurred at 12 weeks after MTX administration. The pattern of changes in the cellularity of the SEP, after misonidazole administration, were similar to those observed after MTX treatment, although the magnitude of the response was reduced. It was concluded that both drugs, but MTX in particular, could have a potential additive effect on glial progenitor cells when used in combination with other forms of cancer therapy including radiation.

Animals↗

PubMed1995

Comparative assessment of single-dose and fractionated boron neutron capture therapy.

The effects of fractionating boron neutron capture therapy (BNCT) were evaluated in the intracerebral rat 9L gliosarcoma and rat spinal cord models using the Brookhaven Medical Research Reactor (BMRR) thermal neutron beam. The amino acid analog p-boronophenylalanine (BPA) was administered prior to each exposure to the thermal neutron beam. The total physical absorbed dose to the tumor during BNCT using BPA was 91% high-linear energy transfer (LET) radiation. Two tumor doses of 5.1 Gy spaced 48 h apart (n = 14) or three tumor doses of 5.2 Gy, each separated by 48 h (n = 10), produced 43 and 70% long-term (> 1 year) survivors, respectively [corrected]. The outcome of neither the two nor the three fractions of radiation was statistically different from that of the corresponding single-fraction group. In the rat spinal cord, the ED50 for radiation myelopathy (as indicated by limb paralysis within 7 months) after exposure to the thermal beam alone was 13.6 +/- 0.4 Gy. Dividing the beam-only irradiation into two or four consecutive daily fractions increased the ED50 to 14.7 +/- 0.2 Gy and 15.5 +/- 0.4 Gy, respectively. Thermal neutron irradiation in the presence of BPA resulted in an ED50 for myelopathy of 13.8 +/- 0.6 Gy after a single fraction and 14.9 +/- 0.9 Gy after two fractions. An increase in the number of fractions to four resulted in an ED50 of 14.3 +/- 0.6 Gy. The total physical absorbed dose to the blood in the vasculature of the spinal cord during BNCT using BPA was 80% high-LET radiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Amelioration of both early and late radiation-induced damage to pig skin by essential fatty acids.

PURPOSE: To evaluate the possible role of essential fatty acids, specifically gamma-linolenic and eicosapentaenoic acid, in the amelioration of early and late radiation damage to the skin. METHODS AND MATERIALS: Skin sites on the flank of 22-25 kg female large white pigs were irradiated with either single or fractionated doses (20 F/28 days) of beta-rays from 22.5 mm diameter 90Sr/90Y plaques at a dose rate of approximately 3 Gy/min. Essential fatty acids were administered orally in the form of two 'active' oils, So-1100 and So-5407, which contained gamma-linolenic acid and a mixture of that oil with eicosapentaenoic acid, respectively. Oils (1.5-6.0 ml) were given daily for 4 weeks prior, both 4 weeks prior and 10-16 weeks after, or in the case of one single dose study, just for 10 weeks after irradiation. Control animals received a 'placebo' oil, So-1129, containing no gamma linolenic acid or eicosapentaenoic acid over similar time scales before and after irradiation. Acute and late skin reactions were assessed visually and the dose-related incidence of a specific reaction used to compare the effects of different treatment schedules. RESULTS: A reduction in the severity of both the early and late radiation reactions in the skin was only observed when 'active' oils were given over the time course of the expression of radiation damage. Prior treatment with oils did not modify the radiation reaction. A 3.0 ml daily dose of either So-1100 or So-5407 given prior to, but also after irradiation with single and fractionated doses of beta-rays produced the most significant modification to the radiation reactions, effects consistent with dose modification factors between 1.06-1.24 for the acute reactions of bright red erythema and/or moist desquamation, and of 1.14-1.35 for the late reactions of dusky/mauve erythema and dermal necrosis. There was the strong suggestion of an effect produced by the 'placebo' oil, So-1129, after higher daily doses of oil. CONCLUSIONS: Essential fatty acids can modulate normal tissue reactions when given over the time when radiation damage is normally expressed. Dose modification factors suggest that a > or = 10% higher dose is required to produce the same level of normal tissue injury. Clinical application of selected essential fatty acids at appropriate doses may lead to a significant increase in the therapeutic gain in patients treated for cancer by radiotherapy.

Animals↗

PubMed1994

Boron neutron capture therapy: a guide to the understanding of the pathogenesis of late radiation damage to the rat spinal cord.

PURPOSE: Before the commencement of new boron neutron capture therapy (BNCT) clinical trials in Europe and North America, detailed information on normal tissue tolerance is required. In this study, the pathologic effects of BNCT on the central nervous system (CNS) have been investigated using a rat spinal cord model. METHODS AND MATERIALS: The neutron capture agent used was 10B enriched sodium mercaptoundecahydro-closododecaborate (BSH), at a dosage of 100 mg/kg body weight. Rats were irradiated on the thermal beam at the Brookhaven Medical Research Reactor. The large spine of vertebra T2 was used as the lower marker of the irradiation field. Rats were irradiated with thermal neutrons alone to a maximum physical absorbed dose of 11.4 Gy, or with thermal neutrons in combination with BSH, to maximum absorbed physical doses of 5.7 Gy to the CNS parenchyma and 33.7 Gy to the blood in the vasculature of the spinal cord. An additional group of rats was irradiated with 250 kVp X rays to a single dose of 35 Gy. Spinal cord pathology was examined between 5 and 12 months after irradiation. RESULTS: The physical dose of radiation delivered to the CNS parenchyma, using thermal neutron irradiation in the presence of BSH, was a factor of two to three lower than that delivered to the vascular endothelium, and could not account for the level of damage observed in the parenchyma. CONCLUSION: The histopathological observations of the present study support the hypothesis that the blood vessels, and the endothelial cells in particular, are the critical target population responsible for the lesions seen in the spinal cord after BNCT type irradiation and by inference, after more conventional irradiation modalities such as photons or fast neutrons.

Animals↗

PubMed1994

Response of the central nervous system to boron neutron capture irradiation: evaluation using rat spinal cord model.

The response of the central nervous system to boron neutron capture irradiation, with either p-boronophenylalanine (BPA) or borocaptate sodium (BSH) as neutron capture agents, has been assessed using a rat spinal cord model. The mean latency times for the development of myelopathy after irradiation with the thermal neutron beam-alone, or in combination with BPA or BSH, were 23.7 +/- 0.3, 21.8 +/- 0.4 and 19.6 +/- 0.4 weeks, respectively. The radiation-induced lesion in the spinal cord was characterised by white matter necrosis. Due to the variations in the microdistribution of different neutron capture agents in body tissues, it was considered inappropriate to define the biological effectiveness of the high LET radiation, resulting from the 10B(n, alpha)7Li neutron capture reaction, relative to photon radiation, using the term 'relative biological effectiveness' (RBE). The term 'compound biological effectiveness' (CBE) factor was used as an alternative. ED50 values for the various irradiation modalities were calculated from probit fitted dose effect curves. Expressed as total physical absorbed doses these values were 13.6 +/- 0.4, 30.3 +/- 2.7 and 13.8 +/- 0.5 Gy after irradiation with the thermal neutron beam alone, or the thermal neutron beam in combination with BSH or BPA, respectively. The RBE of the thermal neutron beam was 1.4 +/- 0.04. The microdistribution of the two neutron capture agents played a crucial role in the determination of the overall biological effect, after thermal neutron activation. BSH, which is excluded from the CNS parenchyma by the blood brain barrier, had a low CBE factor value of 0.46 +/- 0.5. BPA, on the other hand, which crosses the blood brain barrier and distributes in the CNS parenchyma, had a higher CBE factor value of 1.33 +/- 0.16.

Absorption↗

PubMed1994

Response of rat skin to boron neutron capture therapy with p-boronophenylalanine or borocaptate sodium.

The effects of boron neutron capture irradiation employing either BPA or BSH as neutron capture agents has been assessed using the dorsal skin of Fischer 344 rats. Pharmacokinetic studies, using prompt gamma spectrometry, revealed comparable levels of boron-10 (10B) in blood and skin after the intravenous infusion of BSH (100 mg/kg body wt.). The 10B content of blood (12.0 +/- 0.5 micrograms/g) was slightly higher than that of skin (10.0 +/- 0.5 micrograms/g) after oral dosing with BPA. Biphasic skin reactions were observed after irradiation with the thermal neutron beam alone or in combination with BPA or BSH. The time of onset of the first phase of the skin reaction, moist desquamation, was approximately 2 weeks. The time at which the second-wave skin reaction, dermal necrosis, became evident was dose-related and occurred after a latent interval of > or = 24 weeks, well after the acute epithelial reaction had healed. The incidence of both phases of skin damage was also dose-related. The radiation doses required to produce skin damage in 50% of skin sites (ED50 values) were calculated from dose-effect curves and these values were used to determine relative biological effectiveness (RBE) and compound biological effectiveness (CBE) factors for both moist desquamation and dermal necrosis. It was concluded on the basis of these calculations that the microdistribution of the two neutron capture agents had a critical bearing on the overall biological effect after thermal neutron activation. BSH, which was possibly excluded from the cytoplasm of epidermal cells, had a low CBE factor value (0.56 +/- 0.06) while BPA, which may be selectively accumulated in epidermal cells had a very high CBE factor (3.74 +/- 0.7). For the dermal reaction, where vascular endothelial cells represent the likely target cell population, the CBE factor values were comparable, at 0.73 +/- 0.42 and 0.86 +/- 0.08 for BPA ad BSH, respectively.

Administration, Oral↗

PubMed1994

Radiation-induced changes in the kinetics of glomerular and tubular cells in the pig kidney.

Both kidneys of 13 mature female Large White pigs were irradiated with a single dose of 9.8 Gy 60Co gamma rays. The pigs were killed serially between 2 to 24 weeks after irradiation. One hour prior to sacrifice bromodeoxyuridine (BrdU) (500 mg/pig) was injected intravenously. At postmortem the kidneys were removed and tissue was taken to prepare cell suspensions. The labeling index (LI) of these suspensions was determined using flow cytometry. In vivo BrdU incorporation in tubular and glomerular cells was determined immunohistochemically. The kinetics of glomerular and tubular cells was evaluated by counting the number of labeled cells/glomerulus and the number of labeled tubular cells/field of view. An average of 1200 glomeruli and 1500 fields of view/time were counted. Similar analyses were performed on renal tissue from unirradiated control animals. Flow cytometry revealed rapid and significant increases in the LI of kidney cells; 2 weeks after irradiation the LI increased from a control value of 0.18 +/- 0.01 to 1.23 +/- 0.22% (P < 0.001). By 4 weeks the maximal value of 2.45 +/- 0.36% was seen; the LI then declined progressively but at 24 weeks after irradiation still remained significantly above control values (P < 0.001). A similar pattern of response was determined by counting the labeled glomerular and tubular cells identified immunohistochemically. However, the increase in labeled glomerular cells occurred 2 weeks after irradiation, whereas that for the tubules occurred 4 weeks after irradiation. These findings indicate that irradiation of the kidney, classically regarded as a "late-responding" organ, is associated with rapid and significant changes in the kinetics of both tubular and glomerular cells.

Animals↗

PubMed1993

The modulation of radiation-induced damage to pig skin by essential fatty acids.

The ability of essential fatty acids (EFAs) to modulate radiation-induced normal tissue injury was assessed in pig skin. Female Large White pigs (approximately 25 Kg) received 3 ml/day orally of either an 'active' oil [So-1100, containing 9% gamma-linolenic acid (GLA)] or a 'placebo' oil (So-1129) for just 4 weeks before or for 4 weeks before and for 16 weeks after irradiation; localised irradiation of skin was with single doses of beta-rays from 22.5 mm diameter 90Sr/90Y plaques. The severity of the acute reaction, assessed in terms of erythema or moist desquamation, was significantly less in those pigs that received So-1100 both before and after irradiation, as compared with those receiving that oil only prior to irradiation and the 'placebo' groups. Dose modification factors (DMFs) of between 1.13-1.24 were obtained. A similar reduction in the severity of acute skin injury was seen in pigs receiving So-1100 for only 10 weeks after irradiation. Late skin damage, assessed in terms of late erythema or dermal necrosis, was also reduced with So-1100, with DMFs of 1.14-1.51. No such modification was observed if So-1100 was only administered for 4 weeks prior to irradiation. No adverse side-effects were apparent as a result of EFA administration. So-1100 may represent a safe and valuable method of increasing the therapeutic gain in radiotherapy.

Animals↗

PubMed1993

Radiation response of mouse lip mucosal epithelium: a cell kinetic study.

Changes in the cell proliferation kinetics of the epithelium of mouse lip mucosa have been assessed after local irradiation with a single dose of 18 Gy of 60Co gamma-rays. By the fifth day after irradiation, two distinct sub-populations of epithelial cells could be discerned. The larger of the two populations consisted of cells exhibiting varying degrees of radiation-induced damage, and the smaller population was composed of cells of normal size and appearance, intermingled between the radiation-damaged cells. There was a progressive decline in the epithelial cell density with time after irradiation, and focal denudation was seen after 11 days. Cell colonies were evident in the remnants of the epithelium by day 7. Degenerate cells could be identified in the basal layer of the mucosal epithelium, both before and after irradiation. The proportion of degenerate cells was increased 5 days after irradiation with the maximum number, approximately 3.6% being counted on days 7 and 8. In the first 2 days after irradiation, there was a reduction in the labelling index (LI) of basal cells in the epithelium. This was followed by recovery to control values on day 3. The LIs of both the radiation-damaged cells and those with a normal appearance remained relatively constant between days 5 and 11, at approximately 10 and approximately 60%, respectively. The LI of basal cells in the cell colonies was very high (approximately 70%). The estimated turnover time (TT) for the basal cell population with a normal appearance and for those in cell colonies (groups of normal cells with a cord length > or = 10 cells), was extremely short < 1 day. There was some fluctuation in TT values for basal cells exhibiting radiation-induced damage, with the shortest value (approximately 3 days) at 7 and 8 days after irradiation. It was concluded from the cell kinetic data that repopulation of the lip mucosal epithelium started between 3 and 5 days after irradiation and the overall response of the mucosa to irradiation was consistent with that predicted by a hierarchical model of cell proliferative organization.

Animals↗

PubMed1993

Boron neutron capture therapy: long-term effects on the skin and spinal cord of the rat.

Our studies of the pharmacokinetics of boron focused on the variations in the concentration in blood of Sprague-Dawley rats with time after the administration of single intravenous doses of 50-200 mg/kg of 10B-enriched sodium mercaptoundecahydro-closo-dodecaborate (BSH). After the lowest dose of BSH there was a progressive decline in the boron content of the blood, with a biological half-life (t1/2) of approximately 4.5 h. Higher doses of BSH resulted in slower boron clearance rates. A dose of 100 mg/kg of BSH was the maximum safely tolerated by the rats. The boron content of the skin at this dose of BSH was a factor of 0.6 lower than that in the blood. To determine the dose-related changes in the response of the central nervous system to BNCT-type radiation exposures, a well-established and clinically relevant model, the rat spinal cord, was used. The spinal cords (20 mm field length) of rats, infused with 100 mg/kg of BSH, were irradiated for 3 to 5 h with cold thermal neutrons from the H6 beam on the DIDO reactor (AERE, Harwell). The skin surface neutron flux was 4.8 x 10(8) n/cm2/s. Exposure times of > or = 4 h resulted in vigorous, biphasic skin reactions, indicative of long-term vascular damage in the dermis. Rats were monitored closely for 84 weeks after irradiation. No abnormal neurological responses were observed and there was no histological evidence of lesions in the spinal cord at the end of the study. These findings indicate that the central nervous system has a high tolerance to BNCT-type radiation using BSH as the neutron capture agent.

Animals↗

PubMed1992

The influence of methotrexate on radiation-induced damage to different lengths of the rat spinal cord.

An experimental model in the rat has been used to assess the possible enhancement of damage to the spinal cord when radiation is given in the presence of methotrexate (MTX). The dose of MTX used, 4 mg/kg, was the maximum dose that could be given to the rat, when administered into the cerebral spinal fluid circulation, without risk of serious neurological effects. Lengths of 4, 8 and 16 mm of the cervical spine were irradiated with single doses of X rays. For animals that developed paralysis within 30 weeks, caused predominantly by the presence of white matter necrosis, there was no evidence to indicate that MTX enhanced the radiation response of the rat spinal cord, at least at a more clinically relevant level of effect i.e. a low incidence of paralysis. However, for the doses associated with the 50% level of effect (ED50) to an 8 mm long field a significant (p less than 0.005) enhancement of the response was seen, suggesting a dose modification factor of 1.19 +/- 0.07. This was interpreted in terms of an hypothesis to explain the well documented volume effect for very small fields in the rat spinal cord which is based on the migration of viable cells in the periphery of the irradiated site. The apparent smaller effect seen when only 4 mm of the spine was irradiated might be related to the nature of the lesion induced at doses required to produce paralysis in these small fields; the lesions were not restricted to white matter but were more severe and also involved the grey matter and nerve roots after a slightly shorter latent period.

Animals↗

PubMed1991

Electron transport in cytochromes P-450 by covalent switching.

The mechanism of electron transfer in cytochrome P-450cam is presented in terms of a covalent switching mechanism. We present a model of putidaredoxin built by homology, which helps explain protein-protein interactions. The mechanism is general enough to account for the genetic variations found in the superfamily of cytochromes P-450. The detail should assist in the design of novel P-450 inhibitors and may have wider implications. The sequence analysis supports our protein model, and highlights the role of cystein and aromatic residues in electron-transport mechanisms. Eukaryotic cytochromes P-450 appear to have evolved their own intramolecular tryptophan electron-transfer mediator, unlike prokaryotic P. putida P-450cam, which still relies upon the C-terminal tryptophan of its attendant electron-transport protein, putidaredoxin. On this basis our protein model is capable of rationalizing the transfer of electrons from NADH to the active site of P-450. At the electronic level the covalent switching that transfers pairs of electrons not only provides a plausible mechanism, but may also have ramifications in a wider context.

Animals↗

PubMed1991

Cross-regulation between G-protein-coupled receptors. Activation of beta 2-adrenergic receptors increases alpha 1-adrenergic receptor mRNA levels.

Stimulation of DDT1 MF-2 vas deferens cells with epinephrine resulted in a time- and dose-dependent loss of alpha 1-adrenergic receptor-specific ligand binding. Regulation of alpha 1-adrenergic receptor mRNA was characterized. In monolayer culture, cells displayed 0.7 +/- 0.05 amol of alpha 1-adrenergic receptor mRNA/microgram of total cellular RNA. Epinephrine, which acts at both alpha 1- and beta 2-adrenergic receptors of DDT1 MF-2 cells, induced a short term (2-8 h) increase (50-70%) in the abundance of alpha 1-adrenergic receptor mRNA. Propranolol, a beta 2-adrenergic receptor antagonist, attenuated the epinephrine-mediated increase in alpha 1-adrenergic receptor mRNA but did not affect the decrease in alpha 1-adrenergic receptor-specific ligand binding. Phentolamine, an alpha 1-adrenergic receptor antagonist, did not attenuate the epinephrine-mediated increase in alpha 1-adrenergic receptor mRNA at 4 h but did block the decrease in alpha 1-adrenergic receptor-specific ligand binding. The half-life of the alpha 1-adrenergic receptor mRNA was approximately 7 h in untreated cells as well as in cells challenged with epinephrine. The epinephrine-promoted increase in alpha 1-adrenergic receptor mRNA was found to result from cross-regulation via beta 2-adrenergic receptors. Cholera toxin, forskolin, as well as the cyclic AMP analog CPT cAMP (8-(4-chlorophenylthio)adenosine 3':5'-cyclic monophosphate) increased the alpha 1-adrenergic receptor mRNA at 4 h, as did epinephrine in the presence of alpha 1-antagonists but not in the presence of a beta-adrenergic antagonist. This is the first report of heterologous up-regulation of mRNA levels of adrenergic receptors. Cross-regulation between alpha 1- and beta 2-adrenergic receptor-mediated pathways at 4 h occurs at the level of mRNA whereas later down-regulation of alpha 1-receptor mRNA and binding proceed via agonist activation of alpha 1-adrenergic receptors.

Animals↗