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J L Thomas

Publications and source records attributed to J L Thomas.

At least 55 records · Page 3Linked to original sources
PubMed1999

The antigonadotropic activity of a 19-nor-progesterone derivative is exerted both at the hypothalamic and pituitary levels in women.

We have previously shown in postmenopausal women that a 19-nor-progesterone derivative, nomegestrol acetate (NOMA) had a strong antigonadotropic activity and that this effect was not mediated via the androgen receptor. The aim of the present study was to further assess the action of this progestin on gonadotropin secretion in women. To demonstrate at which level of the hypothalamo-pituitary-ovarian axis the gonadotropin inhibition was exerted, 10 normally cycling (NC) women, 3 women with a gonadotropin-independent ovarian function [McCune-Albright (MCA) syndrome], and 5 women with functional hypothalamic amenorrhea (FHA) participated in the study. NC women were treated orally with 5 mg NOMA for 21 days, after one control cycle. Plasma estradiol (E2) and progesterone, LH, and FSH levels were measured during each cycle. A frequent sampling study (every 10 min for 4 h), followed by a classic GnRH test (100 microg, i.v.), was performed on day 11. Women with MCA were studied before, during NOMA, and after long-acting GnRH agonist administration. In women with FHA, pulsatile GnRH (20 microg s.c., every 90 min) was given for two cycles with or without NOMA (5 mg for 21 days). In all NC women, ovulation was suppressed by NOMA. Mean plasma LH levels, LH pulse frequency, and the LH response to exogenous GnRH were significantly decreased. In MCA, neither NOMA nor GnRH agonist modified multiple ovarian cysts on ultrasound or plasma E2, levels which remained elevated, ruling out a direct ovarian effect. In FHA, pulsatile GnRH administration recreated a normal ovulatory menstrual cycle. Addition of NOMA prevented the increase of plasma E2, decreased the amplitude of LH pulses, and prevented ovulation. In view of this unexpected action of NOMA at the pituitary level, seven samples of normal human female pituitaries were tested for the presence of progesterone receptor (PR) using a double labeling immunocytochemical technique. The presence of PR was detected in the seven human pituitary tissues. In addition, PR was found to be expressed only in gonadotroph cells. In conclusion, NOMA, a 19-nor-P derivative, has a potent antigonadotropic activity exerted at the hypothalamic level, inhibiting ovulation in NC women. In women with FHA, NOMA decreased the gonadotropin stimulation induced by pulsatile GnRH administration. According to the presence of PR in gonadotroph cells of normal human pituitaries, 19-nor-progesterone derivatives may also act on the gonadotropin secretion at the pituitary level.

Adolescent↗
PubMed1999

Creation of a fully active, cytosolic form of human type I 3beta-hydroxysteroid dehydrogenase/isomerase by the deletion of a membrane-spanning domain.

Human 3beta-hydroxysteroid dehydrogenase/steroid Delta(5)-Delta(4)-isomerase (3beta-HSD/isomerase) is a bifunctional, single enzyme protein that is membrane-bound in the endoplasmic reticulum (microsomes) and mitochondria of cells in the placenta (type I) and in the adrenals and gonads (type II). Two membrane-binding domains (residues 72-89 and 283-310) have been predicted by analyses of hydrophobicity in the type I and II isoenzymes (90% regional homology). These putative membrane domains were deleted in the cDNA by PCR-based mutagenesis, and the two mutant enzymes were expressed by baculovirus in insect Sf9 cells. Differential centrifugation of the Sf9 cell homogenate containing the 283-310 deletion mutant revealed that 94% of the 3beta-HSD and isomerase activities were in the cell cytosol, 6% of the activities were in the microsomes, and no activity was in the mitochondria. This is the opposite of the subcellular distribution of the wild-type enzyme with 94% of the activities in the microsomes and mitochondria and only 6% activity in the cytosol. The organelle distribution of the 72-89 deletion mutant lies between these two extremes with 72% of the enzyme activity in the cytosol and 28% in the microsomes/mitochondria. The integrity of the subcellular organelle preparations was confirmed by electron microscopy. Western immunoblots confirmed the presence of the 283-310 deletion mutant enzyme and the absence of the wild-type enzyme in the insect cell cytosol. The unpurified, cytosolic 383-310 deletion mutant exhibited 3beta-HSD (22 nmol/min per mg) and isomerase (33 nmol/min per mg) specific activities that were comparable with those of the membrane-bound, wild-type enzyme. The isomerase reaction of the cytosolic 283-311 deletion mutant requires activation by NADH just like the isomerase of the microsomal or mitochondrial wild-type enzyme. In contrast, the 72-89 deletion mutant had low 3beta-HSD and isomerase specific activities that were only 12% of the wild-type levels. This innovative study identifies the 283-310 region as the critical membrane domain of 3beta-HSD/isomerase that can be deleted without compromising enzyme function. The shorter 72-89 region is also a membrane domain, but deletion of this NH(2)-terminal region markedly diminishes the enzyme activities. Purification of the active, cytosolic 283-310 deletion mutant will produce a valuable tool for crystallographic studies that may ultimately determine the tertiary/quaternary structure of this key steroidogenic enzyme.

Amino Acid Sequence↗
PubMed1999

The Vineberg legacy: internal mammary artery implantation from inception to obsolescence.

At a time when cardiac surgery was still approached with hesitation, Arthur M. Vineberg developed the procedure of direct implantation of the internal mammary artery into the left ventricle for the relief of myocardial ischemia. The Vineberg operation, as it became known, had merit but never received broad endorsement from the medical and surgical communities. Its physiologic benefits were inconsistent and for years were documented by little more than anecdotal evidence, until coronary angiography (newly developed by Mason Sones) was able to demonstrate that the procedure did in fact increase perfusion in the diseased heart. This supporting evidence came rather late, for within the next decade direct aortocoronary artery bypass grafting overtook the Vineberg operation as a more efficient means of revascularizing the myocardium. Thousands of patients, however, had benefited from internal mammary artery implantation at a time when options were few; and the procedure was an aggressive move towards current (and similarly aggressive) treatments for myocardial ischemia. Moreover, the characteristics of the myocardium that Vineberg sought to exploit may form the basis for future therapy. A reappraisal of the implant is warranted, as today's physicians and surgeons inherit the last remaining recipients of Vineberg implants.

Coronary Angiography↗
PubMed1999

Coronary artery bypass and superior vena cava syndrome.

Superior vena cava syndrome is the obstruction of the superior vena cava or its main tributaries by benign or malignant lesions. The syndrome causes edema and engorgement of the vessels on the face, neck, and arms, nonproductive cough, and dyspnea. We discuss the case of a 48-year-old obese diabetic woman who was admitted with unstable angina. She had previously been diagnosed with superior vena cava syndrome. Urgent coronary artery bypass grafting was necessary Although thousands of coronary artery bypasses are performed every year, there are not many reports on patients with superior vena cava syndrome who successfully undergo cardiopulmonary bypass and coronary artery grafting with an internal mammary artery as the conduit. The results of the case and alternative recommended methods are discussed.

Angina, Unstable↗
PubMed1998

B7.1 is a quantitatively stronger costimulus than B7.2 in the activation of naive CD8+ TCR-transgenic T cells.

Using a TCR transgenic mouse bred onto a recombinase-activating gene-2-deficient background, we have examined the influence of B7.1 and B7.2 on activation of naive, CD8+ T cells in vitro. We found that B7.1 was a more potent costimulus than B7.2 for induction of proliferation and IL-2 production by naive CD8+ T cells. This difference appeared to be quantitative in nature, as determined using transfectants expressing various defined levels of B7.1 or B7.2, or using purified B7.1 or B7.2 fusion proteins. In contrast to the quantitative differences seen in stimulation of naive T cells, B7.1 and B7.2 were comparable in their ability to costimulate responses in T cells previously primed in vitro. In addition, primed, but not naive, T cells were capable of proliferating and producing IL-2 in response to a TCR stimulus alone, apparently in the absence of B7 costimulation. Lastly, we found that B7.1 and B7.2 were equivalently capable of driving differentiation of naive CD8+ T cells into an IL-4-producing phenotype when exogenous IL-4 was added to the primary culture or to an IFN-gamma-producing phenotype in the presence of IL-12. These results indicate that signals generated by B7.1 and B7.2 are qualitatively similar, but that B7.1 is quantitatively stronger than B7.2. Further, our results indicate that the activation state of the responding T cell may influence the efficiency with which the T cell can respond to a costimulatory signal provided by either B7.1 or B7.2.

Animals↗
PubMed1998

Multiple restricted origin of oligodendrocytes.

The plp gene encodes the proteolipid protein and its alternatively spliced product DM-20, major proteins of CNS myelin. In the mouse, plp/dm-20 transcripts are expressed beginning at embryonic day 9.5 (E9.5) by restricted foci of germinative neuroepithelial cells. To determine the identity of the neural precursors expressing plp/dm- 20, a zeomycin resistance gene fused to the lacZ reporter was expressed in transgenic mice under the control of the plp regulatory sequences. In the three different lines generated, the pattern of beta-galactosidase expression was similar and superimposable on the expression pattern of endogenous plp/dm-20. Both in vivo and in vitro, the transgene was expressed by O4(+) pre-oligodendrocytes, and later by RIP+ differentiated oligodendrocytes, but not by neuronal cells, astrocytes, or radial glial cells. After zeomycin selection, a dramatic enrichment in O4(+) pre-oligodendrocytes was observed in cultures derived from E12.5 transgenic embryos. This enrichment indicates the oligodendroglial specification of neural precursors that continuously express plp/dm-20. Early plp/dm-20-expressing precursors, however, appear to be a separate population from previously described PDGFRalpha oligodendrocyte precursors, as shown by the striking differences in their (1) patterns of distribution and (2) responsiveness to PDGF. These data suggest that oligodendrocytes have a plural origin and that early plp/dm-20 defines one of the neural lineages generating oligodendrocytes.

Animals↗
PubMed1998

Coronary artery disease in women. A historical perspective.

Knowledge about the natural history of coronary heart disease in women was limited until recent years. Few studies included women, despite the fact that heart disease is the No. 1 cause of death in women older than 50 years and the cause of about 500,000 deaths annually. Over the past decade, knowledge has increased owing to a combination of greater participation of women in medical studies, improved medical technology, and political pressure. While much remains to be learned, researchers have found that coronary artery disease in women typically follows a different course than it does in men. Women's risk factors also differ from men's, in part owing to the key protective role played by estrogen. Increasing knowledge about women and heart disease can provide new tools for physicians caring for women at risk of heart disease.

Clinical Trials as Topic↗
PubMed1998

Site-directed mutagenesis identifies amino acid residues associated with the dehydrogenase and isomerase activities of human type I (placental) 3beta-hydroxysteroid dehydrogenase/isomerase.

3beta-hydroxysteroid dehydrogenase/steroid delta5-->4-isomerase (3beta-HSD/isomerase) was expressed by baculovirus in Spodoptera fungiperda (Sf9) insect cells from cDNA sequences encoding human wild-type I (placental) and the human type I mutants - H261R, Y253F and Y253,254F. Western blots of SDS-polyacrylamide gels showed that the baculovirus-infected Sf9 cells expressed the immunoreactive wild-type, H261R, Y253F or Y253,254F protein that co-migrated with purified placental 3beta-HSD/isomerase (monomeric Mr=42,000 Da). The wild-type, H261R and Y253F enzymes were each purified as a single, homogeneous protein from a suspension of the Sf9 cells (5.01). In kinetic studies with purified enzyme, the H261R mutant enzyme had no 3beta-HSD activity, whereas the Km and Vmax values of the isomerase substrate were similar to the values obtained with the wild-type and native enzymes. The Vmax (88 nmol/min/mg) for the conversion of 5-androstene-3,17-dione to androstenedione by the Y253F isomerase activity was 7.0-fold less than the mean Vmax (620 nmol/min/mg) measured for the isomerase activity of the wild-type and native placental enzymes. In microsomal preparations, isomerase activity was completely abolished in the Y253,254F mutant enzyme, but Y253,254F had 45% of the 3beta-HSD activity of the wild-type enzyme. In contrast, the purified Y253F, wild-type and native enzymes had similar Vmax values for substrate oxidation by the 3beta-HSD activity. The 3beta-HSD activities of the Y253F, Y253,254F and wild-type enzymes reduced NAD+ with similar kinetic values. Although NADH activated the isomerase activities of the H261R and wild-type enzymes with similar kinetics, the activation of the isomerase activity of H261R by NAD+ was dramatically decreased. Based on these kinetic measurements, His261 appears to be a critical amino acid residue for the 3beta-HSD activity, and Tyr253 or Tyr254 participates in the isomerase activity of human type I (placental) enzyme.

Amino Acid Sequence↗
PubMed1998

Focusing and steering through absorbing and aberrating layers: application to ultrasonic propagation through the skull.

The time-reversal process is applied to focus pulsed ultrasonic waves through the human skull bone. The aim here is to treat brain tumors, which are difficult to reach with classical surgery means. Such a surgical application requires precise control of the size and location of the therapeutic focal beam. The severe ultrasonic attenuation in the skull reduces the efficiency of the time reversal process. Nevertheless, an improvement of the time reversal process in absorbing media has been investigated and applied to the focusing through the skull [J.-L. Thomas and M. Fink, IEEE Trans. Ultrason. Ferroelectr. Freq. Control 43, 1122-1129 (1996)]. Here an extension of this technique is presented in order to focus on a set of points surrounding an initial artificial source implanted in the tissue volume to treat. From the knowledge of the Green's function matched to this initial source location a new Green's function matched to various points of interest is deduced in order to treat the whole volume. In a homogeneous medium, conventional steering consists of tilting the wave front focused on the acoustical source. In a heterogeneous medium, this process is only valid for small angles or when aberrations are located in a layer close to the array. It is shown here how to extend this method to aberrating and absorbing layers, like the skull bone, located at any distance from the array of transducers.

Brain Neoplasms↗
PubMed1998

Magnesium isotopic abundance measurement in humans: comparison of two mass spectrometric methods.

Pharmacokinetic studies using stable isotopes of magnesium as tracers need to determine the isotopic abundance in biological media by means of mass spectrometry. Of mass spectrometric techniques, electronic impact-mass spectrometry (EI-MS) and inductively coupled plasma-mass spectrometry (ICP-MS) can be used. We have measured the isotopic abundance in plasma and urinary samples and compared the precision and accuracy of these two methods. Graphical representations showed that mean differences were close to 0, there was no obvious relationship between the difference and the mean, and no systematic bias was evidenced at low or high isotopic abundance. This was shown for isotopic abundance of either 25 Mg and 26 Mg. EI-MS is able to measure magnesium isotopic abundance with an intra-day precision between 0.14 and 0.45 per cent and with an inter-day precision between 0.20 and 1.23 per cent. ICP-MS exhibited an intra-day precision between 0.01 and 0.06 per cent and an inter-day precision between 0.01 and 0.15 per cent. Our results showed that, despite the similar isotopic abundances in biological samples obtained with the two methods, a large difference in precision clearly favours ICP-MS in studies of magnesium behaviour using stable isotopes.

Biological Availability↗
PubMed1997

In situ expression of PLP/DM-20, MBP, and CNP during embryonic and postnatal development of the jimpy mutant and of transgenic mice overexpressing PLP.

We analyzed by in situ hybridization the spatiotemporal expression of dm-20, myelin basic protein (MBP) and 2'-3' cyclic nucleotide phosphodiesterase (CNP) during embryonic and postnatal development of the normal mouse and two plp/dm-20 mutants: the jimpy mouse and a transgenic mouse overexpressing the plp gene. In the central nervous system (CNS) of the normal mouse, dm-20 mRNA was detected at embryonic day (E)9.5 in the laterobasal plate of the diencephalon. The pattern of expression of CNP transcript was superimposable on that of dm-20, but appeared slightly later, at E12.5. MBP mRNA was detected even later (E14.5), and, in addition, only in the caudal (rhombencephalon and spinal cord) territories of expression of dm-20 and CNP. These observations support our previous proposals: (1) dm-20-expressing cells in the germinative neuroepithelium are precursors of oligodendrocytes, and (2) oligodendrocytes emerge from distinct pools of precursors along the neural tube (Timsit et al., 1995). In the jimpy mutant, despite the mutation in the plp gene, cells of the oligodendrocyte lineage developed normally. It is only at the time of myelin deposition that oligodendrocytes die. During embryonic development of the transgenic mutant overexpressing plp, there were no alterations in the spatiotemporal pattern or the level of expression of dm-20 in the CNS, in contrast to the higher levels of dm-20 observed in the peripheral nervous system (PNS).

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1997

[Topical hormonal treatment and urogenital atrophy].

Hypoestrogenemia-derived urogenital symptoms after menopause manifest after some years of hormonal deficit and appear commonly in elderly, untreated women. In the urogenital tract low postmenopausal estrogen levels lead to vaginal irritation and dryness and to dyspareunia, often accompanied by other symptoms like uriesthesis, incontinence or recurrent infections. Every systemic estrogen treatment is accepted as efficient for the correction of urogenital symptoms, often even at doses lower than those necessary for the correction of vasomotor symptoms. Diverse local treatments have been proposed: estriol, promestriene and low-dose estrone or estradiol. Promestriene applied locally stimulates differentiation and maturation of vaginal mucosa and compensates local hypoestrogenic effects without marked hormonal effects outside the vagina. Vaginal application of estrone, on the other hand, has rather been proposed for systemic hormone substitution and elevated levels of estrone and estradiol observed in the plasma render this method in-appropriate in cases where strictly local effects are desired. Recently, very low doses of estradiol in a range of 7.5 micrograms/day have been proposed for the treatment of urogenital atrophy by means of a prolonged release regimen. Among the described preparations, those with strictly local (devoid of systemic) effects should be restricted to patients with contraindications for systemic substitution therapy. Local estrogen therapies are recommended for the treatment of complaints due to vulvar and vaginal atrophy. They have also been proposed by certain authors for the acceleration of the cervico-vaginal and vulvar cicatrisation after surgical interventions or postpartum. The presence of miction disorders in elderly postmenopausal women is also a point in favour of local treatment.

Administration, Intravaginal↗
PubMed1997

Affinity radiolabeling identifies peptides associated with the isomerase activity of human type I (placental) 3beta-hydroxysteroid dehydrogenase/isomerase.

3beta-Hydroxysteroid dehydrogenase and steroid Delta5-->4-isomerase (3beta-HSD/isomerase) were purified as a single protein from human term placenta. The affinity alkylator, 5,10-secoestr-4-yne-3,10, 17-trione (secosteroid), was incubated with the purified enzyme (30/1 secosteroid/enzyme molar ratio) to produce an 80% loss of initial isomerase activity over 90 min in a time-dependent, irreversible manner. The secosteroid inactivated 3beta-HSD by only 20% during the same 90 min. Incubations containing the isomerase substrate steroid, 5-androstene-3,17-dione, completely protected the isomerase activity from inactivation by the secosteroid and did not slow the inactivation of 3beta-HSD. The enzyme containing covalently bound steroid was separated from unreacted secosteroid by reversed phase HPLC. Ketones on the protein-bound secosteroid were radiolabeled by reduction with sodium boro[3H]hydride (specific radioactivity 50 microCi/micromol for the transferred tritium). After removal of the unreacted sodium boro[3H]hydride, the affinity-radiolabeled enzyme was digested with trypsin-TPCK, and the peptides were isolated by reversed phase HPLC. The radiolabeled peptide fractions were sequenced. The secosteroid alkylated three tryptic peptides: 251GQFYYISDDTPHQSYDNLNYTLSK274, tritiated His262; 176NGGTLYTCALR186, tritiated Cys183; and 353TVEWVGSLVDR363, tritiated Trp356. Coincubation with the isomerase substrate blocked the labeling of these three peptides and shifted the alkylation by secosteroid to a single tryptic peptide (135EIIQNGHEEEPLENTWPAPYPHSK159, tritiated His142). Using substrate protection to validate specificity, the affinity labeling secosteroid has identified peptides in the enzyme that are associated with isomerase activity.

Affinity Labels↗
PubMed1997

PMP-22 expression in the central nervous system of the embryonic mouse defines potential transverse segments and longitudinal columns.

PMP-22, a major constituent of peripheral nervous system (PNS) myelin, is also present in the central nervous system (CNS), in motoneurons of the cranial nerve motor nuclei and spinal cord (Parmantier et al. [1995] Eur. J. Neurosci. 7:1080-1088). The expression of PMP-22 in the CNS during embryonic and early postnatal development was investigated and showed a biphasic spatio-temporal pattern. The expression of PMP-22 started at embryonic day (E)11.5, in restricted longitudinal and transverse domains, in the ventricular zone of the spinal cord, rhombencephalon, mesencephalon and prosencephalon. In the mid- and forebrain, the PMP-22 signal was detectable in a longitudinal domain that followed ventrally the basal/alar boundary but could no longer be detected dorsally at some distance from the roof plate. Along the caudo-rostral axis, the territory in which PMP-22 was detected spanned the mesencephalon and the prosencephalon, extending caudally from the limit between the isthmus and the mesencephalon, and rostrally to the boundary between prosomeres 4 and 5 (p4/p5). In agreement with the prosomeric model of forebrain organization proposed by Puelles and Rubenstein ([1993] TINS 16:472-479), differences in the level of PMP-22 expression in p2, p3, and p4 clearly defined the p2/p3 and p3/p4 neuromeric boundaries. By E17.5, PMP-22 was no longer detected in the ventricular zone, but at E18.5 it began to be expressed in motoneurons of cranial nerve motor nuclei and, after birth, following a rostro-caudal gradient, in the ventral spinal cord.

Animals↗
PubMed1997

Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium.

OBJECTIVE: To compare the effects on endometrium, climacteric symptoms and the menstrual cycle, and the clinical and biological tolerance of two percutaneous oestradiol gels used as hormone replacement therapy. DESIGN: A large open randomised multicentre study. SETTING: France and Belgium. PARTICIPANTS: Two-hundred and fifty-four women with an intact uterus and who had experienced a natural menopause received either Oestrogel (n = 126) or Estreva, a new formulation of oestradiol gel (n = 128), (1.5 mg of oestradiol/day) for the 24 first days of each calendar month during six consecutive months. Nomegestrol acetate (Lutenyl), a norprogesterone derivative, was administered (5 mg/day) from day 11 to day 24 of each oestradiol cycle. MAIN OUTCOME MEASURES: Examination of endometrial biopsies taken before treatment and between days 18 and 24 of the last treatment cycle, climacteric symptoms assessed using a modified Kupperman index, control of menstrual cycle evaluated by diary cards, and clinical and biological tolerance. RESULTS: Both treatments lowered the frequency and intensity of hot flushes and the global Kupperman index. 96% of the cycles were followed by withdrawal bleeding. Breakthrough bleeding or spotting resulted in premature discontinuation of treatment in one volunteer. Mastodynia occurred in 20 women and contributed to the premature termination of treatment in three of them. Endometrial biopsies taken at the end of treatment showed identical histologies in both groups, with a secretory pattern in the majority of women, and absence of hyperplasia. CONCLUSIONS: This trial confirmed that, when the two oestradiol gels tested were administered cyclically with nomegestrol acetate to postmenopausal women, they were well tolerated, effective and suitable for the treatment of oestrogen deficiency syndrome.

Administration, Cutaneous↗
PubMed1997

[Comparative study of the short-term acceptability and tolerance of a new oral formulation of magnesium (TX 1341) and a reference magnesium].

This open, randomized study on 2 parallel groups compared the acceptability, digestive tolerance and observance of TX 1341, a new chewable magnesium tablet (OROMAG, Laboratoire Théramex) to that of a reference magnesium (MAG2, Laboratoire Théraplix). 179 patients warranting a magnesotherapy were treated for 10 weeks either by 3 chewable lactate and citrate of magnesium tablets (TX 1341) each containing 120 mg of magnesium-element, or by 3 drinkable ampoules of pidolate of magnesium (each of 122 mg of magnesium-element). Acceptability was assessed at the end of the study by a semi-quantitative scale at four levels and digestive tolerance by closed questionnaire submitted before and after treatment. 72.7% of patients treated by TX 1341 find the treatment agreeable against 46.1% with the reference magnesium (p < 0.01). The number of drops out linked to treatment is not significantly different in the two groups and they are virtually all linked to digestive problems. The two medications significantly lower the number of cases of constipation without noticeably increasing the number of cases of diarrhea. The comparison of the number of digestive symptoms which appeared under treatment only underline one significant difference between the 2 groups (p < 0.05): the appearance of 5 times less the number of abdominal pains with TX 1341 (2 cases). Cases of irregular intake are significantly higher with the reference drug than with TX 1341 (respectively 23.7% and 8.5%; p < 0.01).

Administration, Oral↗
PubMed1996

Kinetics of membrane micellization by the hydrophobic polyelectrolyte poly(2-ethylacrylic acid).

Rates of pH-dependent micellization of multilamellar vesicles by the hydrophobic polyelectrolyte poly(2-ethylacrylic acid) (PEAA) have been measured turbidometrically. This polymer shows a strong ph-dependence in its affinity for phospholipid membranes, binding in increasing amounts as pH is lowered and ultimately solubilizing membranes to form mixed micelles (Tirrell, Takigawa and Seki (1985) Ann. N.Y. Acad. Sci. 446, 237). The rate of solubilization of dipalmitoylphosphatidylcholine (DPPC) vesicle suspensions by PEAA increases approximately linearly with reductions in pH below a threshold at pH 6.55. Interestingly, negatively-charged dipalmitoylphosphatidylglycerol membranes showed qualitatively similar behavior in the presence of PEAA, and incorporation of 10% or 20% dipalmitoylphosphatidic acid in DPPC membranes did not affect solubilization rates, demonstrating that membrane charge is not an important factor in determining micellization kinetics. Micellization of DPPC and dimyristoylphosphatidylcholine membranes occurs most rapidly at their respective gel-liquid crystalline transition temperatures (Tm); the rate enhancement is correlated with a peak in the temperature-dependent binding of a fluorescently-modified PEAA in slightly alkaline solutions in which no micellization is observed. The lateral compressibility of the membrane, which has a similar peak at Tm, is proposed to be an important determinant of the rate and extent of polymer adsorption, and consequently of the rate of micellization.

1,2-Dipalmitoylphosphatidylcholine↗