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Biomedical subjects

G Siest

Publications and source records attributed to G Siest.

439 records · Page 25Linked to original sources
PubMedDate not supplied

[Drug conjugation in the brain].

Several drugs and environmental pollutants can cross the blood-brain barrier and reach the brain. This organ possesses an enzymatic equipment able to metabolize xenobiotics, therefore facilitating their elimination and maintaining brain homeostasis. This metabolism may result in the formation of toxic metabolites, which endanger neuronal integrity and may result in neurological disturbances. The main function of the conjugation enzymes present in the brain parenchyma and blood-brain or blood-cerebrospinal fluid interfaces is the detoxification of these reactive molecules, thus protecting the central nervous system. This review presents the main cerebral conjugating enzymes, and shows the interest for the design of new drugs of the knowledge of their activities.

Acetyltransferases↗
PubMedDate not supplied

Identification of cytochrome P-450 isozymes involved in the hydroxylation of dantrolene by rat liver microsomes.

The role of individual rat liver cytochrome P-450 isozymes in the metabolism of the skeletal muscle relaxant, dantrolene, was studied. Following incubation of dantrolene with hepatic microsomes from 3-methylcholanthrene-treated rats, two major hydroxylated metabolites were identified. Using inhibitory antibodies specific for individual cytochrome P-450 isozymes, cytochromes P-450 1A1, 1A2, and 3A were identified to be involved in dantrolene hydroxylations. In liver microsomes from 3-methylcholanthrene-treated rats, antibodies specific for cytochrome P-450 1A1 and 1A2 inhibited hydroxylation of dantrolene by 60% and 20%, respectively. Kinetics studies using these microsomes showed that dantrolene hydroxylation was biphasic with a low KM (0.06-0.08 microM) and high KM (5-7 microM). Cytochrome P-450 1A1 was responsible for the low KM hydroxylation of dantrolene, whereas cytochrome P-450 1A2 was responsible for the high KM. In hepatic microsomes from pregnenolone-16 alpha-carbonitrile-treated rats, an antibody specific for cytochrome P-450 3A completely inhibited the formation of 5-hydroxydantrolene, the major metabolite formed by these microsomes.

Animals↗
PubMedDate not supplied

In vitro irreversible binding of ketoprofen glucuronide to plasma proteins.

Many aryl alkanoic acids are cleared as ester glucuronide excreted in urine. While conjugation with glucuronic acid is generally considered as a detoxication process, this conjugate has been shown over the past decade to be a potentially reactive metabolite, undergoing hydrolysis, intramolecular rearrangement, and irreversible binding to proteins. This study describes the in vitro degradation of biosynthetic ketoprofen glucuronide after incubation with human plasma, human serum albumin solutions at various concentrations (290 and 580 microM), and in protein-free buffer, in physiological conditions (pH = 7.4, 37 degrees C). The protein concentrations chosen correspond to that found in synovial fluid and plasma, respectively. Albumin catalyzed the hydrolysis of the glucuronide, but the extent of the reaction was not dependent on the protein concentration. The irreversible binding of ketoprofen was investigated in identical conditions. Maximal ketoprofen-adduct concentrations were achieved after 3 and 10 hr incubation, and were 6.65, 3.2, and 2.6% of initial ketoprofen in plasma and albumin solutions at 580 and 290 microM, respectively. The difference in binding between plasma and albumin (580 microM) could not be totally attributed to the other major plasma proteins, because no irreversible binding was detected with fibrinogen and gamma globulins, and only 0.14% of ketoprofen was bound to alpha and beta globulins after 3 hr incubation. The covalent interaction with albumin was proportional to conjugate concentration over the range studied (from 5 to 30 micrograms/ml or 11.62 to 69.72 microM).

Blood Proteins↗
PubMedDate not supplied

[Alzheimer disease: hypotheses implicating apolipoproteins E].

The most promising discovery in the study of Alzheimer's disease (AD) markers is undoubtedly the implication of apolipoprotein E (apoE). The gene of this apoliprotein is located on chromosome 19 and is characterized by three common alleles epsilon 2, epsilon 3 and epsilon 4 giving raise to 6 genotypes and 6 protein phenotypes. ApoE is well known for its role in cholesterol transport. Different studies have been performed, giving major arguments in favor of an important role of apoE in the pathophysiology of AD. These include the discovery of the relationship between the epsilon 4 allele and AD, the ability of this protein to form complexes with beta amyloid protein (A beta) in seniles plates, its presence in neurofibrillary tangles and in vessels of AD patients. Another important finding is the differential interaction between the different isoforms of apoE and tau protein. Some of the hypotheses implicate the role of different apoE isoforms on the growth and extension of neurones, perhaps by a receptor mediated pathway. It has been suggested that apoE acts as a pathological chaperone protein, or alternatively that it protects neurons by regulation of the cell membrane and modifying calcium homeostasis. It is clear that apoE genotype determination alone cannot be used for diagnosis of AD. The presence of epsilon 4 allele is only one of several risk factors for the development of the disease. Other factors may also be implicated and are the subject of ongoing research.

Alzheimer Disease↗
PubMedDate not supplied

[Criteria for addition of apolipoprotein B measurement during routine health screening examinations: validation in a Stanislas cohort. The Biologist's Group of the Health Examination Center].

The purpose of this study was to determine the criteria in which apolipoproteins AI and B should be performed during periodic health screening examinations. Clinically, the results of apolipoproteins AI and B are most useful when there are minor lipid perturbations (cholesterol and triglycerides), but their routine determination is not justified. Several mathematical models, defined by discriminate factorial analysis, have been studied. The one based uniquely on cholesterol and triglyceride concentrations was the most efficient in identifying patients in whom apolipoprotein B should be determined. In contrast, no model was found for the indication of apolipoprotein AI determination. Data from a population different from that used for the model establishment were used to validate the model. This strategy, determining criteria for additional measurement of apolipoprotein B in a general population, is of clinical interest because it may provide complementary information for subjects with atherogenic risk. Moreover, it is of economical interest because it has the potential of limiting complementary testing and its associated costs.

Adult↗