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S Benhamou

Publications and source records attributed to S Benhamou.

At least 55 records · Page 3Linked to original sources
PubMed1998

Association between lung cancer and microsomal epoxide hydrolase genotypes.

Microsomal epoxide hydrolase (mEH) is involved in the metabolism of tobacco-derived carcinogens. Polymorphisms in exons 3 and 4 of the EPHX gene have been reported to be associated with variations in mEH activity. We examined whether the predicted mEH activity modified the lung cancer risk among 150 cases and 172 controls, all French Caucasian smokers. A significant association was found between predicted mEH activity and lung cancer (P < 0.02), with a dose-effect relationship (P < 0.005). The risks associated with intermediate and high activities, compared to low activity, were 1.65 (95% CI, 0.95-2.86) and 2.66 (95% CI, 1.33-5.33), respectively. The effect of mEH activity on lung cancer risk was not significantly modified by smoking exposure, CYP1A1 genotype, or GSTM1 genotype. mEH may thus be an important genetic determinant of smoking-induced lung cancer.

Adult↗
PubMed1998

Multicenter case-control study of exposure to environmental tobacco smoke and lung cancer in Europe.

BACKGROUND: An association between exposure to environmental tobacco smoke (ETS) and lung cancer risk has been suggested. To evaluate this possible association better, researchers need more precise estimates of risk, the relative contribution of different sources of ETS, and the effect of ETS exposure on different histologic types of lung cancer. To address these issues, we have conducted a case-control study of lung cancer and exposure to ETS in 12 centers from seven European countries. METHODS: A total of 650 patients with lung cancer and 1542 control subjects up to 74 years of age were interviewed about exposure to ETS. Neither case subjects nor control subjects had smoked more than 400 cigarettes in their lifetime. RESULTS: ETS exposure during childhood was not associated with an increased risk of lung cancer (odds ratio [OR] for ever exposure = 0.78; 95% confidence interval [CI] = 0.64-0.96). The OR for ever exposure to spousal ETS was 1.16 (95% CI = 0.93-1.44). No clear dose-response relationship could be demonstrated for cumulative spousal ETS exposure. The OR for ever exposure to workplace ETS was 1.17 (95% CI = 0.94-1.45), with possible evidence of increasing risk for increasing duration of exposure. No increase in risk was detected in subjects whose exposure to spousal or workplace ETS ended more than 15 years earlier. Ever exposure to ETS from other sources was not associated with lung cancer risk. Risks from combined exposure to spousal and workplace ETS were higher for squamous cell carcinoma and small-cell carcinoma than for adenocarcinoma, but the differences were not statistically significant. CONCLUSIONS: Our results indicate no association between childhood exposure to ETS and lung cancer risk. We did find weak evidence of a dose-response relationship between risk of lung cancer and exposure to spousal and workplace ETS. There was no detectable risk after cessation of exposure.

Aged↗
PubMed1998

Path integration in dogs.

We studied path integration in dogs, Canis familiaris, required to return to the starting point of L-shaped outward paths in the absence of landmark information. The analysis of the distributions of errors in the return direction and distance showed that the dogs made both systematic and random errors. They tended to overestimate by about 6 degrees the amount of turning required at the end of the outward path to take the correct return direction. Random angular errors were characterized by a standard deviation of about 9 degrees. The dogs also tended to underestimate the correct return distance by about 6%, and random distance errors were characterized by a standard deviation of about 13% of the correct return distance. While random errors are assumed to stem simply from inaccuracies in kinaesthetic and vestibular systems, systematic errors are likely to be generated because path integration is implemented at the neural level through approximate rather than mathematically exact solutions. A path integration model in which the moving animal is assumed to overestimate slightly the inferred motion parallax of the starting point can roughly account for the dogs' directional bias, but not for systematic errors in distance estimation. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1998

An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians.

The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism exhibits marked racial heterogeneity, with the poor metabolizer PM phenotype representing 13-23% of oriental populations, but only 2-5% of Caucasian populations. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) have been described, which account for more than 99% of Oriental poor metabolizer alleles but only approximately 87% of Caucasian poor metabolizer alleles. Therefore, additional defects presumably contribute to the poor metabolizer in Caucasians. Recent studies have found a third mutation CYP2C19*4, which accounts for approximately 3% of Caucasian poor metabolizer alleles. A fourth rare mutation (CYP2C19*5A) (C99,A991,Ile331;C1297T,Arg433-->Trp) resulting in an Arg433 to Trp substitution in the heme-binding region has been reported in a single Chinese poor metaboliser outlier belonging to the Bai ethnic group. The present study identifies a second variant allele CYP2C19*5B (C99-->T; A991-->G, Ile331-->Val; C1297-T, Arg433-->Trp in one of 37 Caucasian poor metabolizers. The frequency of the CYP2C19*5 alleles is low in Chinese (approximately 0.25% in the Bai ethnic group) and Caucasians (< 0.9%). However, these alleles contribute to the poor metabolizer phenotype in both ethnic groups and increases the sensitivity of the genetic tests for identifying defective alleles to approximately 100% in Chinese poor metabolizers and 92% in Caucasian poor metabolizers genotyped in our laboratory. The Arg433 to Trp mutation in the heme-binding region essentially abolishes activity of recombinant CYP2C19*5A toward S-mephenytoin and tolbutamide, which is consistent with the conclusion that CYP2C19*5 represents poor metabolizer alleles.

Alleles↗
PubMed1998

N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk.

Acetyltransferases, encoded by the NAT1 and NAT2 genes, are involved in the activation/inactivation reactions of numerous xenobiotics, including tobacco-derived aromatic amine carcinogens. Several allelic variants of NAT1 and NAT2, which cause variations in acetylation capacity, have been detected. The NAT2 slow acetylator phenotype/genotype has been inconsistently associated with lung cancer and, to date, the role of NAT1 polymorphism in lung cancer has not been reported. The effect of NAT1 and NAT2 genetic polymorphisms on individual lung cancer risk was evaluated among 150 lung cancer patients and 172 control individuals, all French Caucasian smokers. The NAT1 alleles (*3, *4, *10, *11, *14, and *15) and the NAT2 alleles (*4, *5, *6, *7) were differentiated by polymerase chain reaction-based restriction fragment length polymorphism methods using DNA extracted from peripheral white blood cells. Genotypes were classified according to current knowledge of the functional activity of the variant alleles. The NAT1*10 and NAT1*11 alleles were considered as rapid alleles, the NAT1*4 and the NAT1*3 as normal alleles and NAT1*14 and NAT1*15 as slow-acetylation alleles. Logistic regression analyses were performed taking into account the age, sex, smoking and occupational exposures. A significant association was observed between lung cancer and NAT1 genotypes (P(homogeneity) < 0.02) with a gene dose effect (P(trend) < 0.01); compared with homozygous rapid acetylators, the lung cancer risk was 4.0 (95% confidence interval 0.8-19.6) for heterozygous rapid acetylators, 6.4 (95% confidence interval 1.4-30.5) for homozygous normal acetylators and 11.7 (95% confidence interval 1.3-106.5) for heterozygous slow acetylators. None of the individuals were homozygous slow acetylators. Similar results were obtained whatever the adjustment considered. No significant association was found between NAT2 genotype and lung cancer. The NAT1 polymorphism may thus be an important modifier of individual susceptibility to smoking-induced lung cancer.

Acetyltransferases↗
PubMed1998

Role of glutathione S-transferase GSTM1, GSTM3, GSTP1 and GSTT1 genotypes in modulating susceptibility to smoking-related lung cancer.

Glutathione S-transferases GSTM1, GSTM3, GSTP1 and GSTT1 are involved in the detoxification of active metabolites of several carcinogens in tobacco smoke. We studied the potential role of GSTM3 and GSTP1 gene polymorphisms either separately, or in combination with GSTM1 and GSTT1 gene polymorphisms, in susceptibility to lung cancer using peripheral blood DNA from 150 lung cancer patients and 172 control individuals, all regular smokers. The frequencies of GSTM3, AA, AB and BB genotypes were 70.7%, 24.0% and 5.3% in cases and 72.7%, 24.4% and 2.9% in control individuals respectively. The frequencies of GSTP1, AA, AG and GG genotypes were 44.7%, 44.0% and 11.3% in cases and 50.0%, 37.2% and 12.8% in control individuals respectively. When studied separately, neither GSTM3 nor GSTP1 genotypes contributed significantly to the risk of lung cancer. Although failing to reach statistical significance, the combined GSTM3 AA and GSTP1 (AG or GG) genotype conferred a nearly threefold risk when the GSTM1 gene was concurrently lacking (odds ratio 2.9, 95% confidence interval 0.7-12.1). Significant interactions were observed between pack-years of smoking and the combined GSTM3 AA and GSTP1 (AG or GG) genotype, or the combined GSTM3 AA, GSTP1 (AG or GG) and GSTM1 null genotype. The combination of these three a priori at risk genotypes conferred an increased risk of lung cancer among smokers with a history of at least 35 pack-years (odds ratio 2.7, 95% confidence interval 1.2-6.0), but not in lighter smokers, probable because of the lower average number of pack-years of smoking found among control individuals with this genotype combination.

Aged↗
PubMed1998

A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin.

The 4'-hydroxylation of the S-enantiomer of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism shows marked interracial heterogeneity, with the poor metabolizer (PM) phenotype representing 2 to 5% of Caucasian and 13 to 23% of Asian populations. Two defective CYP2C19 alleles, CYP2C19*2 and CYP2C19*3, have been described which account for approximately 87% of Caucasian and > 99% of Oriental PM alleles. The present study identifies a new allele (CYP2C19*4) in Caucasian PMs which contains an A-->G mutation in the initiation codon. A new polymerase chain reaction-restriction fragment length polymorphism genotyping test was developed, and the incidence of this allele was examined in a European Caucasian population which had been phenotyped for mephenytoin metabolism. One of nine putative PMs was heterozygous for CYP2C19*2/CYP2C19*4, which suggests that CYP2C19*4 represents a defective allele. Six of the seven remaining putative PMs available for genotyping were explained by CYP2C19*2. The frequency of the CYP2C19*4 allele in Caucasians was 0.6%. An additional Caucasian PM from a separate study was also heterozygous for CYP2C19*2 and CYP2C19*4. To verify that CYP2C19*4 represented a defective CYP2C19 allele, the initiation codon of the normal CYP2C19*1 cDNA was mutated to a GTG, and both cDNAs were expressed in yeast. Recombinant CYP2C19 protein was detected by Western blot analysis of colonies transformed with CYP2C19*1 cDNA, but not in those transformed with CYP2C19*4 cDNA. The two cDNAs were also used in an in vitro coupled transcription/translation assay. CYP2C19 protein was translated only from the CYP2C19*1 allele. These data indicate that CYP2C19*4 represents a new PM allele.

Alleles↗
PubMed1998

Larynx cancer risk in relation to glutathione S-transferase M1 and T1 genotypes and tobacco smoking.

Glutathione S-transferase (GST) isoenzymes are involved in the detoxification of several tobacco smoke-derived carcinogens. It is thus conceivable that deficiency in GST activity due to homozygous deletion of the GSTM1 and GSTT1 genes (the null genotypes) may modulate susceptibility to smoking-induced cancers. The effects of the GSTM1 and GSTT1 null genotypes on laryngeal cancer risk were evaluated using peripheral blood DNA from 129 larynx cancer patients and 172 noncancer controls, all of whom were regular smokers. Increased larynx cancer risk was related to the GSTM1 null genotype [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.0-2.8]. The OR associated with the GSTT1 null genotype was increased, although not significantly (OR = 1.4, 95% CI = 0.7-2.9). Individuals with concurrent lack of GSTM1 and GSTT1 genes had a doubled, although not significant, risk for larynx cancer when compared with those having at least one of these genes (OR = 2.0, 95% CI = 0.8-5.2) and had almost a 3-fold risk (OR = 2.7, 95% CI = 1.0-7.4) when compared with those with both genes. Moreover, a significant interaction between the GSTM1 genotype and levels of tobacco consumption (P < 0.05) was found; the GSTM1 null genotype was associated with an increased risk of larynx cancer among smokers of 20 g/day or less (OR = 2.9, 95% CI = 1.3-6.3) but not among heavier smokers (OR = 1.0; 95% CI = 0.5-2.0). In contrast, the GSTT1 null genotype posed an increased, although not significant, risk among long-term smokers (OR = 2.3, 95% CI = 0.9-5.4).

Aged↗
PubMed1998

Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin.

A genetic polymorphism in the metabolism of the anticonvulsant drug S-mephenytoin has been attributed to defective CYP2C19 alleles. This genetic polymorphism displays large interracial differences with the poor metabolizer (PM) phenotype representing 2-5% of Caucasian and 13-23% of Oriental populations. In the present study, we identified two new mutations in CYP2C19 in a single Swiss Caucasian PM outlier (JOB 1) whose apparent genotype (CYP2C19*1/CYP2C19*2) did not agree with his PM phenotype. These mutations consisted of a single base pair mutation (G395A) in exon 3 resulting in an Arg132-->Gln coding change and a (G276C) mutation in exon 2 resulting in a coding change Glu92-->Asp. However, the G276C mutation and the G395A mutation resided on separate alleles. Genotyping tests of a family study of JOB1 showed that the exon 2 change occurred on the CYP2C19*2 allele, which also contained the known splice mutation in exon 5 (this variant is termed CYP2C19*2B to distinguish it from the original splice variant now termed CYP2C19*2A). The exon 3 mutation resided on a separate allele (termed CYP2C19*6). In all other respects this allele was identical to one of two wild-type alleles, CYP2C19*1B. The incidence of CYP2C19*6 in a European Caucasian population phenotyped for mephenytoin metabolism was 0/344 (99% confidence limits of 0 to 0.9%). Seven of 46 Caucasian CYP2C19*2 alleles were CYP2C19*2B(15%) and 85% were CYP2C19*2A. The Arg132Gln mutation was produced by site-directed mutatgenesis and the recombinant protein expressed in a bacterial cDNA expression system. Recombinant CYP2C19 6 had negligible catalytic activity toward S-mephenytoin compared with CYP2C19 1B, which is consistent with the conclusion that CYP2C19*6 represents a PM allele. Thus, the new CYP2C19*6 allele contributes to the PM phenotype in Caucasians.

Alleles↗
PubMed1997

Path integration by swimming rats

Path integration is a process that enables a moving animal to memorize the location of the starting point of its outward path relative to its current position by continuously processing motion-related information collected en route (route-based information). There has been no evidence, however, that path integration could be used by a swimming animal, even in aquatic or amphibious species. I conducted water maze experiments to test whether rats, Rattus norvegicuscan rely on path integration while swimming, in order to return to a hidden escape platform after circular outward paths ranging from 60&deg; to 300&deg;. Rats proved able to perform the task in a few days. No systematic errors in the distribution of return directions could be observed. In contrast, there was a fairly large random error (about 55&deg;), which, surprisingly, did not depend on the outward path length. Comparison with walking rats could not be made because of the lack of published data. However, results for walking hamsters, Mesocricetus auratusshowed that their random errors are slightly smaller than those made by swimming rats. Such large errors are likely to prevent rats as well as hamsters (and presumably any swimming or walking mammal) from using path integration over long outward paths.

Journal Article↗
PubMed1997

The neuropsychology of spatial cognition in the rat.

This article provides a review of the neural mechanisms of spatial cognition in the rat. A survey of the literature shows that the rat has spatial capabilities that can be explained only if one assumes that it possesses a representation of some features of the environment. The scope of such a representation may, however, be more limited than what is implied by the hypothesis of a bird's-eye view of the environment. The best documented spatial ability of the rat is illustrated by its efficiency in performing the water maze navigation task. A review of recent neurobiological data collected while a rat was performing this task suggests that several brain structures make unique contributions to spatial navigation. In particular, the hippocampal formation and the associative (posterior) parietal cortex seem to handle different aspects of navigation and to be differentially involved in the various stages of spatial memory formation. Electrophysiological data support the hypothesis that the hippocampal formation is concerned with rapidly building associative memories of spatial relationships within the environment. In contrast, the associative parietal cortex might be involved in more abstract spatial processing, resulting in a metric representation of spatial information collected during movements.

Animals↗
PubMed1996

The effect of tobacco on lung cancer risk depends on CYP2D6 activity.

The genetically determined P450 CYP2D6 activity is suspected to be involved in lung carcinogenesis by activating carcinogens contained in tobacco smoke. Therefore, lung cancer risk should depend on both smoking exposure and CYP2D6 activity. The extent to which CYP2D6 activity, determined by using dextromethorphan, could modify the effect of tobacco was evaluated from a study on 128 lung cancers and 157 controls. A strong interaction was observed; the effect of tobacco on lung cancer risk rose with increasing CYP2D6 activity (P < 0.001). Increasing levels of smoking increased lung cancer risk only among smokers with the highest CYP2D6 activity, and CYP2D6 was a risk factor only among heavy smokers. Smokers with both the highest CYP2D6 activity and daily tobacco consumption were at very high risk for lung cancer. These results may explain discrepant results of previous studies on the association between CYP2D6 activity and lung cancer.

Age Factors↗
PubMed1996

Effects of CYP2D6 activity and tobacco on larynx cancer risk.

The genetically determined capacity of the cytochrome P450 CYP2D6 is suspected to be involved in the activation of tobacco carcinogens. From a multicentric case-control study carried out to analyze the interaction between host and environmental factors on tobacco-related cancers, we reported recently that the effect of tobacco on lung cancer risk rose with increasing CYP2D6 activity, and the effect of CYP2D6 activity rose with increasing tobacco consumption. The aim of the present report was to investigate whether results on lung cancer could be observed for larynx cancer, from a study on 140 cases and 157 controls. A weak interaction between increasing levels of both CYP2D6 activity and average daily consumption of tobacco was found (P = 0.12). The only significant interaction between these two factors was observed when CYP2D6 activity was considered with the two conventional phenotypes (P < 0.05). A dose-response effect of tobacco on larynx cancer risk was found only among one-third of the smokers with the highest level of CYP2D6 activity, and CYP2D6 was a risk factor only among heavy smokers. The highest risk for larynx cancer was then observed among smokers having both the highest levels of CYP2D6 activity and daily consumption of tobacco. The interaction between CYP2D6 activity and tobacco was weaker for larynx cancer than that reported previously for lung cancer. However, the similarities in the results found for these two cancers, i.e., a greater effect of tobacco among smokers with the highest CYP2D6 activity, reinforce the hypothesis that this activity could modify the effect of tobacco on cancer risk.

Aged↗
PubMed1996

[Procedures of vital status obtention in a cohort born in France].

To know if included patients in a study are alive or dead is essential. In practice, the knowledge of vital status is a pre-requisite to the collection of the medical cause of death in epidemiology. In clinical research all investigators, particularly those in cancerology, must recuperate this information for all patients lost to follow-up. There are two methods to obtain the vital status of a subject: to have access to the civil status register of the local town hall where the subject was born, or to contact the "Institut National de la Statistique et des Etudes Economiques" (INSEE). We describe each of these procedures: ways to put them into practice, their efficacy and problems encountered. To write to town halls is a simple efficient method and is advised when the number of sujects is small, but this procedure poses a problem of confidentiality. The examination of the tapes of registered deaths from INSEE is recommended for many querries concerning a lot of subjects.

Cohort Studies↗