Cytochrome P450 et activation génétique — de la pharmacologie à l’élimination du cholestérol et à la régression de l’athérosclérose

Background

Lipoproteins are closely associated with the atherosclerotic vascular process. Elevated levels of highdensity lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apo AI) in plasma indicate a low probability of coronary heart disease (CHD) together with enhanced longevity, and elevated levels of low-density lipoproteincholesterol (LDL-C) and apo B indicate an increased risk of CHD and death. Studies linking gene activation and the induction of cytochrome P450 with elevated plasma levels of apo AI and HDL-C and lowered plasma levels of LDL-C presented a new potential approach to prevent and treat atherosclerotic disease.

Objective and methods

This is a review aimed at clarifying the effects of P450-enzymes and gene activation on cholesterol homeostasis, the atherosclerotic vascular process, prevention and regression of atherosclerosis and the manifestation of atherosclerotic disease, particularly CHD, the leading cause of death in the world.

Results

P450-enzymes maintain cellular cholesterol homeostasis. They respond to cholesterol accumulation by enhancing the generation of hydroxycholesterols (oxysterols) and activating cholesterol-eliminating mechanisms. The CYP7A1, CYP27A1, CYP46A1 and CYP3A4 enzymes generate major oxysterols that enter the circulation. The oxysterols activate — via nuclear receptors — ATP-binding cassette (ABC) A1 and other genes, leading to the elimination of excess cholesterol and protecting arteries from atherosclerosis. Several drugs and nonpharmacologic compounds are ligands for the liver X receptor, pregnane X receptor and other receptors, activate P450 and other genes involved in cholesterol elimination, prevent or regress atherosclerosis and reduce cardiovascular events.

Conclusions

P450-enzymes are essential in the physiological maintenance of cholesterol balance. They activate mechanisms which eliminate excess cholesterol and counteract the atherosclerotic process. Several drugs and nonpharmacologic compounds induce P450 and other genes, prevent or regress atherosclerosis and reduce the occurrence of non-fatal and fatal CHD and other atherosclerotic diseases.     

Infection génitale à chlamydia chez l’homme et retentissement sur la fécondité

Chlamydia trachomatis is responsible for the most common sexually transmitted disease, up to 40% of the non gonococcal urethritis. It is a compulsary intracellular parasite. Its peculiar metabolism makes the bacteria interfere with the host cell immunity. Infection can become chronic and induce inflammation, if not properly treated, by permanent emission of antigens and heat shock proteins, and stimulation of Tcells. Autoimmunization against sperm can occur and impair fertilization and embryo implantation. Thus, Chlamydial infection can be associated with male infertility because of tissue damage, altered movement and antisperm immunization. PCR and LCR are to date the most sensitive detection techniques for c.trachomatis. Our study aim was to determine the prevalence of Chlamydial infection by PCR in 6 groups of men in andrologic practice. The highest prevalences have been found in the infertile men group and in the symptomatic group. No Chlamydia culture was found positive in any group. The association of PCR with anti C. trachomatis seminal IgA and seric IgG are useful tools for andrologic exploration.     

Imagerie moléculaire de la plaque d’athérome vulnérable. Évaluation préclinique et clinique de traceurs radioactifs

Atherosclerotic cardiovascular diseases (CVD) are the leading cause of mortality worldwide, accounting for greater than 19.10⁶ deaths annually. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. Indeed, an acute heart attack is the first symptom of atherosclerosis in as much as 50% of individuals with severe disease. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerosis in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could potentially allow the identification of vulnerable patients by non-invasive scintigraphic imaging following administration of a radiolabeled tracer. The development of radiolabeled probes that specifically bind to and allow the in vivo imaging of vulnerable atherosclerotic plaques is therefore the subject of intense ongoing experimental and clinical research. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET imaging. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable atherosclerotic plaques in the carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of the coronary arteries remains a challenging issue because of the small size of atherosclerotic lesions and of their vicinity with blood and the circulating tracer activity.     

Profil lipidoprotéinique,isotopique et risque athérogène dans la drépanocytose en Côte d’Ivoire

The principal goal of this study was to assess the possible disturbances of lipids and lipoproteins in sickle cell disease and establish a relationship between painful crisis and atherogenic risks by the atherogenicity index in Ivoirian adults. We analysed serum plasma lipid and lipoprotein profiles of 126 subjects with sickle cell anemia, and 55 “Hb AA” healthy individuals. The lipid and lipoprotein parameters studied were total cholesterol, triglycerids, HDL, LDL, apoproteins A1 and B, electrophoresis of lipoproteins and haemoglobin. In painful crisis, levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, apoproteins A1 (apo A1) in sickle cell anemia patients were shown to be significantly lower and levels of triglycerides higher than that of control group and steady state. The electrophoresis profile showed a significant fall of α lipoproteins while β lipoproteins were significantly high in period of crisis. The atherogenicity index (total cholesterol/HDL ratio) was also significantly high, just as LDL/HDL ratio in period of crisis. The overview of these results might hypothesize a high relatively atherogenic risk during the sickle-cell anemia crisis. A special monitoring of the patients in crisis is also necessary in order to prevent the risk of cardiovascular diseases.     

Cancer et Hérédité

Sans résumé     

Radiopharmaceutiques et réglementations

The radiopharmaceuticals are products that combine two very stringent regulatory requirements from two different authorities: as medicine from a pharmaceutical point of view (Afssaps) and as radioactive source with specific authorization (ASN). This article discusses the different regulatory constraints imposed by these authorities but suggests also that legislation is supposed to be modified in the coming years in collaboration with nuclear physicians and their Society (SFMN).     

Fonction sexuelle et bilan sexologique de i’homme paraplégique et tétraplégique

This paper describes the sexological examination of spinal cord injured men. The complete exam includes a clinical interview, neurological examination, an EMG of the pelvic floor, a urodynamic examination and ano-rectal exploration, and the objective recording of the man’s sexual response to reflex and psychogenic professionals or psychologists and sextherapists can proceed with a more thorough interview which evaluates number of the elements of the physical examination. The results of the investigation give rise to a number of clinical entities described in terms of lesion levels with respect to the innervation of the reproductive system. Lesions can therefore be classified as being located above the two pathways of erection, or extended to the cauda equina. Each lesion type is associated with a given pronostic of erectile and ejaculatory function. The accompanying physiological recording of penile responses further helps to establish a differential diagnosis between an exclusively organic dysfunction or a primarily psychogenic dysfunction in spinal cord injured men.