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Biomedical subjects

M M Galteau

Publications and source records attributed to M M Galteau.

At least 19 recordsLinked to original sources
PubMed2001

Differential regulation of gamma-glutamyltransferase mRNAs in four human tumour cell lines.

Human gamma-glutamyltransferase (GGT) belongs to a multigenic family and at least three mRNAs are transcribed from the gene that codes for an active enzyme. Four human tumour cell lines (HepG2, LNCap, HeLa and U937) with different GGT levels were used to investigate how GGT activity, total GGT mRNA and each individual GGT mRNA subtype responded to tumour necrosis factor-alpha (TNF-alpha), 12-O-tetradecanoylphorbol 13-acetate (TPA) or sodium butyrate treatment. Butyrate reduced the GGT activity in HepG2 cells, and the level of total GGT mRNA accordingly, whereas TNF-alpha and TPA did not alter these parameters. In LNCap cells, TNF-alpha, TPA, and butyrate reduced the activity as well as the level of GGT total mRNA. In HeLa cells no significant changes were observed either in activity or in mRNA level whereas TPA induced both GGT activity and mRNA levels in U937 cells. The distribution of each GGT mRNA subtype (A, B and C) was found to be cell specific: type B mRNA was the major form in HepG2 cells, while type A was the major form in LNCap and HeLa, type A and type C were expressed almost at the same level in U937 cells. The GGT mRNA subtypes were also differently modulated in these cells after TNF-alpha, TPA or butyrate treatment, suggesting that they are regulated by distinct and cell type specific mechanisms.

Butyrates↗
PubMed2001

Acivicin induces apoptosis independently of gamma-glutamyltranspeptidase activity.

Inhibition of cellular gamma-glutamyltranspeptidase (GGT) enzyme activity by its specific inhibitor acivicin is frequently used in studies aimed at demonstrating the physiological role of this enzyme. However, because acivicin is a glutamine antagonist, it also inhibits many other glutamine-dependent enzymes involved in purine and pyrimidine biosynthesis. The objective of the present work is to determine whether acivicin exhibits apoptotic properties and the significance of GGT activity level in the response to acivicin treatment. We compared acivicin (0-150 microM) effect on V79 cell lines expressing or not expressing human GGT. Apoptosis was assayed by annexin-V staining, cell cycle analysis, and caspase activation using flow cytometry. We found that acivicin causes a dose- and time-dependent apoptosis in the GGT-negative V79 cell line as well as in its GGT-positive counterpart line. This is the evidence that acivicin induces apoptosis in V79 cell independently of their GGT activity level.

Animals↗
PubMed2001

Control of apolipoprotein E secretion in the human hepatoma cell line KYN-2.

Even though it is known that apolipoprotein E (apoE) is deeply involved in major age-related disorders such as atherosclerosis or Alzheimer's disease (AD), the control of cell-specific apoE expression is still poorly understood. We compared the apoE secretion as previously described in astrocytic cell17 to hepatic cell apoE secretion. We used the human hepatoma cell line KYN-2 to better delineate the characteristics of apoE secretion and to validate it with respect to the classical human hepatoma cell line HepG2. Interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) significantly inhibited, while IL-2, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were inactive on apoE secretion by KYN-2 as well as HepG2 cells. Cholesterol and 25-OH cholesterol had no effect, while forskolin exerted a significant inhibitory effect, on apoE secretion in KYN-2 cells. Our results suggest that the KYN-2 cell line represents an appropriate cell model, and in any case an alternative model to the HepG2 cell line, to study the control of apoE secretion. The response of KYN-2 cells to both cytokines and cholesterol differs from that found in astrocytoma cells, suggesting that blood variations of apoE concentrations in AD may not reflect the dysregulations taking place in the brain.

Adenylyl Cyclases↗
PubMed2001

Determination of serum cystatin C: biological variation and reference values.

Human cystatin C is a low molecular weight protein which has been proposed as a better marker of glomerular filtration rate than creatinine. To be able to interpret results obtained in different patient populations it is necessary to define cystatin C reference values. We measured serum concentration of cystatin C in 1223 subjects using a particle-enhanced nephelometric assay. Subjects were aged 4 to 79 years and were selected among apparently healthy individuals who came to the Centre for Preventive Medicine in Vandoeuvre-Lès-Nancy, France. We observed a Gaussian distribution of cystatin C concentration in serum. We did not find any effect of age or gender in children, hormonal status in women (puberty, menopause, oral contraceptives or hormone replacement therapy) or alcohol intake. Cystatin C concentration was slightly lower in female than in male adults below the age of 60 years. Cystatin C levels significantly increased above the age of 60 in both males and females, probably due to physiological aging of renal function. No other significant differences were observed between males and females. Using multiple regression analysis, moderate correlations were observed between body mass index and cystatin C, and between smoking and cystatin C, but these were not biologically significant. According to the literature, only methylprednisolone and cyclosporin A increased and decreased cystatin C levels, respectively. The reference values for cystatin C obtained in a carefully selected population were 0.75+/-0.089 mg/l for children aged 4-19 years, 0.74+/-0.100 mg/l for males and 0.65+/-0.085 mg/l for females (aged 20-59 years), and 0.83+/-0.103 mg/l for older individuals (> or =60 years).

Adolescent↗
PubMed2000

Effects of pro-inflammatory cytokines on apolipoprotein E secretion by a human astrocytoma cell line (CCF-STTG1).

Apolipoprotein (apo) E has been implicated in Alzheimer's disease; however, little is known about the regulation of its secretion in astrocytes. To investigate the effects of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on apoE secretion by CCF-STTG1 cells, a sensitive and specific double sandwich Enzyme-Linked ImmunoSorbent Assay (ELISA) was developed. Using a monoclonal anti-human apoE antibody as the capture antibody, this assay was carried out with commercially available reagents. The assay had a sensitivity of 0.013 ng per well, within-run and between-run variation coefficients of 6.0 and 8.6 per cent respectively. There was no cross-reactions between antibodies used and apoAI, apoAII, apoB, apoCI, apoCII and apoCIII. Low apoE concentrations were assessed using a serum-free HepG2 culture medium as secondary calibrator, containing 59 microg l(-1) of apoE. In serum-free medium, CCF-STTG1 cells secreted apoE, the accumulation of which in the cell medium increased linearly with time (27 microg per 48 h). After 48 h of incubation, apoE secretion was inhibited by TNF-alpha but not affected by IL-1beta and IFN-gamma. However, the effect of regulatory factors may depend upon culture conditions since in the presence of 10 per cent fetal calf serum, IFN-gamma significantly inhibited apoE secretion. Thus, apoE secretion by CCF-STTG1 cells is inhibited by specific pro-inflammatory cytokines. This new apoE ELISA presents the great advantage of using commercially available reagents which permit inter-laboratory comparability of results, involves relatively low cost and is adaptable for the measurement of low levels of apoE.

Apolipoproteins E↗
PubMed2000

Short communication. The effects of drinking and smoking on the CYP2D6 metabolic capacity.

We studied the influence of drinking and smoking habits on CYP2D6 metabolic capacity measured by the use of debrisoquine as a substance test. We did not find any significant differences in the frequency of subjects with CYP2D6 deficiency (poor metabolizers) among four groups of healthy individuals: nonsmokers/nondrinkers, smokers/drinkers, nondrinkers/smokers, and nonsmokers/drinkers. We demonstrated that, among poor metabolizers, alcohol and tobacco consumption was associated with higher metabolic ratios than it was with the control group, but the differences were not statistically significant. Among extensive metabolizers, the lowest metabolic ratio (highest enzyme activity) was detected for nondrinkers/smokers, intermediate values for smokers/drinkers, and the highest metabolic ratio (lowest enzyme activity) for nonsmokers/drinkers. These variations were slight but statistically significant when logarithmic ratio values were applied. These results show that smoking and drinking habits do not need to be taken into account when humans are phenotyped for CYP2D6.

Adult↗
PubMed1999

Candidate genetic modifiers of individual susceptibility to renal cell carcinoma: a study of polymorphic human xenobiotic-metabolizing enzymes.

The steady increase in sporadic renal cell carcinoma (RCC) observed in industrialized countries supports the notion that certain carcinogens present in the environment (tobacco smoke, drugs, pollutants, and dietary constituents) may affect the occurrence of RCC. Many of the enzymes dealing with such environmental factors are polymorphic and may, therefore, confer variable susceptibility to RCC. This case-control study was designed to test for an association between genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of sporadic RCC. Genomic DNA was obtained from 173 patients with RCC and 211 controls of Caucasian origin. We used PCR-RFLP to investigate polymorphism for the most common alleles at two cytochrome-P450 mono-oxygenases (CYP1A1 and CYP2D6), one NAD[P]H:quinone oxidoreductase (NQO1), three glutathione S-transferases (GSTM1, GSTT1, and GSTP1), and one N-acetyltransferase (NAT2) loci. The CYP1A1 (m) "variant" genotype, which contains at least one copy of the CYP1A1 variant alleles, was found to be associated with a 2.1-fold [95% confidence interval (CI), 1.1-3.9] increase in the risk of RCC. There was also a higher risk of RCC for subjects with the CYP1A1 (m) variant genotype combined with any of the following genotypes: GSTT1 (+) "active" [odds ratio (OR), 2.3; 95% CI, 1.2-4.5], GSTP1 (m) variant (OR, 2.4; 95% CI, 1.0-5.4), or NAT2 (-) "slow acetylator" (OR, 2.5; 95% CI, 1.1-5.5). A significant association was also found for the GSTM1 (-) "null" and GSTP1 (m) genotypes combined with either NAT2 (-) (OR, 2.6; 95% CI, 1.2-5.8) or CYP1A1 (m) (OR, 3.5; 95% CI, 1.1-11.2). The CYP2D6 (-) "poor metabolizer " and the NQO1 (-) "defective" genotypes were not clearly associated with a higher risk of RCC. Our data demonstrate for the first time a significant association between a group of pharmacogenetic polymorphisms and RCC risk. These positive findings suggest that interindividual variation in the metabolic pathways involved in the functionalization and detoxification of specific xenobiotics is an important susceptibility factor for RCC in Caucasians.

Adult↗
PubMed1996

Evaluation of urinary D-glucaric acid excretion in workers exposed to butyl glycol.

The biological follow-up of subjects exposed to butyl glycol (BG) is generally accomplished using a standard blood count that is not sensitive enough to reveal early intoxication by this molecule. For this reason we have used an indirect test for evaluating the induction of hepatic enzymes, the measurement in urine of D-glucaric acid (DGA), which reflects the activity of the glucuronic acid enzyme pathway. This study was performed on 17 foundry workers exposed to BG emissions coming from paints used in cataphoresis. The airborne concentration of BG was less than 0.3 times the average limit exposure value. This study shows that BG emissions at low concentrations are able to increase the activity of the enzymes of the glucuronic acid pathway. DGA urinary excretion increased by 165% in winter (p < .01) and by 85% (p < .05) in summer when the doors are open and the BG concentration lower. DGA urinary excretion is significantly higher in smoking than in nonsmoking exposed workers. None of these workers had a perturbed blood count. This study shows that the urinary level of DGA provides a good test for the follow-up of exposure to BG in the electrophoresis painting plant, and that the exposed smoking workers seem to be more sensitive to BG exposure than do the nonsmokers. In conclusion, the measurement of urinary DGA might be considered as a useful test for the surveillance of subjects exposed to vapors containing BG.

Adult↗
PubMed1995

Dextromethorphan O-demethylase activity in rat brain microsomes.

CYP2D, a genetically variable isoform of cytochrome P450, has been characterized mainly in the liver and the brain of mammals by measurement of debrisoquine hydroxylase activity. Moreover, 'poor debrisoquine metabolizer' phenotype is significantly increased in Parkinson's disease patients. We present here the first demonstration that the activity of the CYP2D isoform can be characterized in rat brain microsomes by the measurement of dextromethorphan O-demethylase capacity. The cerebral formation of dextrorphan, an antagonist of the N-methyl-D-aspartate receptor, was inhibited by the presence of quinidine and N-methyl-4-phenylpyridinium (MPP+), a dopaminergic neurotoxin inducing a chemical parkinsonism in humans.

Animals↗
PubMed1995

Lipid and lipoprotein genetic variability: an important contribution from the French health examination centers.

OBJECTIVE: To assess lipid and lipoprotein genetic variability in the French Population. METHODS: Many health examination centers are covering a great part of France (700,000 individuals are examined in 54 centers every year). Each citizen has the right to have a personal examination every 5 years. This unique system was modified in 1992, and we are presenting our 25-year experience focusing on the results we have more recently obtained in the lipid and lipoprotein field. RESULTS: First of all, the 600 items of information collected on every patient coming to our Center give us the data and facilitate the development of the theory of reference values. Having mastered the analytical variations, we studied the biological variations. Age, sex, overweight, tobacco, alcohol, and drugs are the main factors we should control for obtaining reference values. More recently, the genetic part in the production of reference values has become of greater importance, particularly for apolipoproteins. Apolipoprotein E is an important lipoprotein for which the two frequent mutations influence the level of circulating Apolipoprotein E. The risks linked to these alleles are also very different in cardiovascular disease and extremely important (for epsilon 4) in Alzheimer's Disease. Apolipoproteins B and A-IV also have interesting polymorphisms, but currently have no systematic applications in clinical chemistry. The familial recruitment we have in Nancy also permitted us to constitute a large tool "La Cohorte Stanislas." CONCLUSION: The thousand families recruited will be followed for 10 years. It is an open tool for collaboration.

Adult↗
PubMed1995

An unequal cross-over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype.

1. The study of the CYP2D genotype and phenotype of a Caucasian family revealed that a XbaI-9 kb allele was associated with the poor metabolizer phenotype. 2. A Polymerase Chain Reaction (PCR)-based assay showed that the previously described mutations D6A and D6B are not associated with the XbaI-9 kb allele. 3. To explore the molecular basis of the poor metabolizer phenotype associated with the XbaI-9 kb allele, complete sequencing of the nine exons and intron-exon boundaries of the CYP2D6 gene was undertaken after amplification by PCR. 4. All the exons were successfully amplified using CYP2D6 gene-specific primers except exon 1 which required a combination of CYP2D7 gene-specific 5' primer and a CYP2D6 gene-specific 3' primer. 5. Sequence data derived from this amplified product revealed that the XbaI-9 kb allele corresponds to a novel rearrangement of the locus. This involved a deletion of an approximately 20 kilobase (kb) DNA segment generating a hybrid 5' CYP2D7/CYP2D6 3' gene. 6. The chimeric gene is non-functional presumably due to an insertion in exon 1 (characteristic of the exon 1 of the CYP2D7 gene) which causes a shift in the reading frame with premature termination of translation.

Base Sequence↗
PubMed1995

[Changes in blood cholesterol levels over a 10-year period; value of a single sample for predicting future blood cholesterol levels].

The aim of this study was to report the serum cholesterol changes over a 10 year period in 12,238 subjects aged 4 to 64 years (mean 28 +/- 14 years) based on 3 health check-ups at an average of 5.5 yearly intervals between 1973 and 1989, and to determine the value of a single sample for predicting the serum cholesterol level at 5 and 10 years, and the influence of blood pressure and Quetelet index on this predictability. After identification of the influencing factors, the different variables were adjusted using a step-by-step regression analysis. The correlation coefficients calculated between the adjusted cholesterol level at the first examination and that measured at 5 and 10 years, were all significant (0.38 to 0.59) and varied with age at the time of the first examination and gender. The positive predictive value of having a cholesterol level higher than the 90th centile at 5 and 10 years when it was already higher than this value at the first examination varied from 26 to 46% respectively with respect to the subgroups. The sensitivity of the test was 25 to 48%. The negative predictive value and specificity were 93 to 95%. The lowering of this threshold to the 80th centile increased the positive predictive value from 35 to 45% and decreased the specificity from 94 to 87% for the whole population. When the first two sampling results, five years apart, were taken into consideration simultaneously, the predictive value of having a raised cholesterol level at 10 years increased from 35 to 61%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

[Reference values of laboratory tests: a useful and important epidemiologic contribution of the Centers for health tests].

Since 1969 the Centre for Preventive Medicine in Nancy has been carrying out health examinations of the eastern region of France (Lorraine, Champagne-Ardenne). The clinical chemists at the Centre of Preventive Medicine have made a great contribution to the concept and the description of biochemical reference values for which the transferability to other health centres must be verified. Knowledge of reference values and biological variations facilitates the interpretation of weak modifications of biological constituents which are observed in preventive medicine. Reference values can be used to compare two populations (comparing reference values between to two) or to compare an individual observed value to the reference values obtained in the various population groups. In the long term, these reference values could become a useful education tool for patients coming for health examination. It should be possible for each subject to follow, throughout his life, the evolution of his biological constituents and to detect any deviation towards a pathology.

Diagnostic Tests, Routine↗
PubMed1995

Apolipoprotein E: an important gene and protein to follow in laboratory medicine.

The human apolipoprotein (apo) E gene is polymorphic, with three common alleles (epsilon 2, epsilon 3, epsilon 4) coding for three isoforms (E2, E3, E4). The isoforms differ from each other by a single amino acid substitution, and also differ in their binding affinity for the four apo E receptors. Apo E polymorphism is an important determinant of risk for the development of cardiovascular and Alzheimer diseases, the prevalence of the epsilon 4 allele being increased in both kinds of patients compared with control subjects. Furthermore, the prevalence of the epsilon 4 allele differs among populations (range 5-40%, respectively, for Taiwanese and Papua New Guineans). Genotyping or phenotyping needs to be introduced in clinical laboratories. The choice of the method should be based on the types of patients who are examined. The apo E genotype is also a determinant of apo E plasma concentration. Standardization of apo E measurement is an important prerequisite before investigating the clinical interest of plasma apo E concentration. Determination of apo E genotype/phenotype and later the plasma concentration are expected to yield useful clinical laboratory information.

Apolipoproteins E↗
PubMed1994

Segregation analyses of four urinary caffeine metabolite ratios implicated in the determination of human acetylation phenotypes.

Human acetylation phenotypes were determined with caffeine (137X) as the test substance, improved by measuring urinary caffeine metabolites with a previously described HPLC method. Caffeine, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (IX), 1-methyluric acid (IU), 1,7-dimethylxanthine (17X), and 1,7-dimethyluric acid (17U) were quantified. This study tested the hypothesis, suggested by previous studies, that the acetylation polymorphism is strongly influenced by a major gene. Phenotypes were assessed by using four urinary caffeine metabolite ratios: AFMU/1X, AFMU/[1X + 1U + 17U], AFMU/[AFMU + 1X + 1U], and AFMU/[1X + 1U + 17X + 17U] in a population included 281 nuclear family members who were healthy volunteer subjects. Each urinary ratio revealed strong familial aggregation with correlations between parents and offspring varying from 0.340 to 0.486 as a function of the ratio considered, and between sibs from 0.410 to 0.512 whereas correlations among spouses were not significant, excluding an effect of environmental factors. Segregation analyses were conducted upon these four ratios testing a series of specific models of inheritance and gave evidence for single locus control of N-acetyltransferase (NAT) activity, with Mendelian codominant transmission using the AFMU/1X, AFMU/[1X + 1U + 17U], and AFMU/[1X + 1U + 17X + 17U] ratios. The slow allelic frequencies were 0.739, 0.753, and 0.724, respectively, and the phenotypic concordance was 90 to 92% with the AFMU/1X ratio. The familial aggregation observed in using the AFMU/[AFMU + 1X + 1U] ratio was consistent with a recessive transmission for the allele controlling the homozygous slow phenotype. This last ratio is not convenient to differentiate rapid heterozygous and homozygous phenotype. Considering the number of misclassified subjects, this study would be completed by genotyping the same families as demonstrated by some authors who predicted 97.5% of acetylation phenotype when using PCR-based DNA amplification test.

Acetylation↗
PubMed1994

DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers.

The molecular basis for DNA haplotype-dependent debrisoquine 4-hydroxylase (CYP2D6) expression was explored by sequencing all of the nine exons of the CYP2D6 gene. Two distinct exon sequence frameworks of the CYP2D6 gene were found, each associated with specific BamHI-defined DNA haplotypes of the CYP2D cluster. They corresponded to Arg296/Cys296 and Ser486/Thr486 amino acid polymorphisms in the CYP2D6 enzyme, and occurred in almost equal frequency among the Caucasians examined. These two major allozymes with amino acid differences in the presumed substrate recognition region and in the vicinity of the heme binding site could be the source of the observed DNA haplotype-dependent variation in phenotypic expression.

Alleles↗
PubMed1994

Drug metabolizing enzymes related to laboratory medicine: cytochromes P-450 and UDP-glucuronosyltransferases.

Many studies on drug metabolism have been carried out during the last decades using protein purification, molecular cloning techniques and analysis of polymorphisms at phenotype and genotype levels. These researchers led to a better understanding of the role of drug metabolizing enzymes in the biotransformation of drugs, pollutants or foreign compounds and of their use in laboratory medicine. The metabolic processes commonly involved in the biotransformation of xenobiotics have been classified into functionalization reaction (phase I reactions), which implicate lipophilic compounds. These molecules are modified via monooxygenation, dealkylation, reduction, aromatization, hydrolysis and can be substrates for the phase II reactions, often called conjugation reactions as they conjugate a functional group with a polar, endogenous compound. This review, devoted to cytochromes P-450 (CYP) and UDP-glucuronosyltransferases (UGT), describes essentially the genetic polymorphisms found in humans, their clinical consequences and the methods to assess the phenotypes or genotypes, with a view to studying the interindividual differences in drug monooxygenation and drug glucuronidation. Variations in drug glucuronidation reported here focused essentially on variations due to physiological factors, induction, drug interactions and genetic factors in disorders such as Gilbert's Syndrome and Crigler-Najjar type I and II diseases.

Cytochrome P-450 Enzyme System↗