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J C Gautier

Publications and source records attributed to J C Gautier.

At least 37 records · Page 2Linked to original sources
PubMed1993

Identification of P450 enzymes involved in metabolism of verapamil in humans.

The calcium channel blocker verapamil[2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6- azaoctanitrile] is widely used in the treatment of hypertension, angina pectoris and cardiac arrhythmias. The drug undergoes extensive and variable hepatic metabolism in man with the major metabolic steps comprising formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile] and norverapamil [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]. The enzymes involved in metabolism of verapamil have not been characterized so far. Identification of these enzymes would enable estimation of both interindividual variability in verapamil metabolism introduced by the respective pathway and potential for metabolic interactions. We therefore characterized the enzymes involved in formation of D-617 and norverapamil. The maximum rate of formation of D-617 and norverapamil was determined in the microsomal fraction of 21 human livers which had been previously characterized for the individual expression of various P450 enzymes (CYP1A2, CYP2C, CYP2D6, CYP2E1 and CYP3A3/4) by means of Western blotting. Specific antibodies directed against CYP3A were used to inhibit formation of D-617 and norverapamil. Finally, formation of both metabolites was investigated in microsomes obtained from yeast cells which were genetically engineered for stable expression of human P450. Formation of D-617 was correlated with the expression of CYP3A (r = 0.85; P < 0.001) and CYP1A2 (r = 0.57; P < 0.01) in the microsomal fraction of 21 human livers after incubation with racemic verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Biotransformation↗
PubMed1993

Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture.

Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CYP1A2, CYP2C, CYP2E1, CYP3A, and epoxide hydrolase in primary human hepatocyte cultures. Steady state P-450 and epoxide hydrolase mRNA levels, as well as ethoxyresorufin-O-deethylase and nifedipine oxidation activities, which are mainly supported by CYP1A1/1A2 and CYP3A, respectively, were measured. Interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha were found to be the most potent depressors of P-450 enzymes. After 3 days of treatment, both mRNA levels and enzyme activities were depressed, typically by at least 40%, whatever the cytokine and the enzyme considered. Interferon-gamma also suppressed CYP1A2 and CYP2E1 mRNA levels and ethoxyresorufin-O-deethylase activity but had no effect on CYP3A and epoxide hydrolase mRNAs. In addition, interleukin-4 had the opposite effect, compared with other cytokines, on CYP2E1 mRNA, which was increased up to 5-fold; ethoxyresorufin-O-deethylase and nifedipine oxidation activities were not significantly affected. These results provide the first demonstration that various cytokines act directly on human hepatocytes to affect expression of major P-450 genes and that a wide range of responses can be observed among the enzymes for a given cytokine, suggesting that different regulatory mechanisms may be involved.

Adult↗
PubMed1993

[Cerebral hemorrhage in migraine].

We report a case of intracerebral hemorrhage which occurred during a migraine in a 62 year-old woman who had migraine since the age of 20. The patient was normotensive. The angiograms were normal. Cerebral hemorrhage in migraine appears to be very rare: we found 6 reported cases that were compared with our own. The hypothesis of recirculation in an infarcted tissue and the possible role of dissecting aneurysms are examined.

Cerebral Hemorrhage↗
PubMed1993

Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites.

The activity of metabolizing enzymes determines plasma concentrations and hence effects of drugs. Identification of these enzymes may allow the prediction of both the interaction potential of drugs and the variability deriving from certain pathways. The antiarrhythmic propafenone is extensively biotransformed to the active metabolites 5-hydroxypropafenone and N-desalkylpropafenone. Whereas 5-hydroxylation is catalyzed by CYP2D6, the enzyme involved in N-dealkylation has not been identified. We, therefore, characterized the enzyme involved in the formation of N-desalkylpropafenone by using both in vitro [human liver microsomes, specific antibodies or inhibitors, and stably expressed cytochrome P450 (P450) enzymes] and in vivo (formation of N-desalkylpropafenone in patients under conditions of chronic therapy) approaches. Formation of N-desalkylpropafenone can be described by Michaelis-Menten kinetics. A strong correlation was observed between maximum rate of formation (Vmax) of N-desalkylpropafenone and the amount of CYP1A2 (r = 0.83, p < 0.001) and CYP3A (r = 0.54, p < 0.05) in the microsomal fraction of 20 human livers. In vitro intrinsic clearances (derived from Vmax/Km) indicated a wide interindividual variability in seven human livers (from 0.01 to 0.1 ml/hr/mg of protein). Antibodies directed against CYP3A and CYP1A2 inhibited formation of N-desalkylpropafenone by 54 +/- 10% and 24 +/- 16%, respectively. The CYP2D6-mediated formation of 5-hydroxypropafenone was unaffected by these antibodies. Verapamil (substrate of CYP3A4 and CYP1A2) and midazolam (substrate of CYP3A4) were competitive inhibitors of N-desalkylpropafenone formation (Ki = 70 microM and 25 microM for verapamil and midazolam, respectively). Coding sequences for CYP1A2 and CYP3A4 were inserted in a yeast expression vector and introduced into Saccharomyces cerevisiae strain W(R). Both CYP1A2 and CYP3A4 catalyzed N-dealkylation of propafenone, with specific activities of 0.32 pmol/min/pmol of P450 and 0.16 pmol/min/pmol of P450, respectively. Our data indicate that N-dealkylation of propafenone is mediated via CYP3A4 and CYP1A2. From experiments on the molecular level interactions of propafenone with other drugs that are metabolized by CYP3A4 and CYP1A2 can be predicted. Such interactions have been reported for cyclosporin, rifampicin, warfarin, and theophylline. Moreover, in vitro intrinsic clearances showed a wide interindividual variability. Therefore, variable plasma concentrations of the active metabolite N-desalkylpropafenone are expected in vivo. We tested this hypothesis in 14 patients (dose of 150 mg of propafenone three times per day) during chronic oral therapy and observed steady state plasma concentrations of N-desalkylpropafenone ranging from 4 to 293 ng/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1993

Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver.

The metabolism of imipramine by human liver microsomes was examined using a combination of five strategies. Human hepatic microsomes produced N-desmethylimipramine (84%), 2-hydroxyimipramine (10%), and 10-hydroxyimipramine (6%). Preincubation of human hepatocytes in culture with beta-naphthoflavone and macrolides exclusively induced the formation of desmethylimpramine (552%, p < 0.05, and 234%, p < 0.003, respectively). Correlations were obtained between rates of imipramine demethylation and cytochrome P-450 (P-450) 1A2 (r = 0.88, p < 0.001) and P-450 3A (r = 0.80, p < 0.02) concentrations in human liver microsomal preparations from 13 different subjects. Anti-P-450 1A2 and anti-P-450 3A antibodies selectively inhibited N-demethylation (80% and 60%, respectively). N-Demethylation was completely inhibited when anti-1A2 and anti-3A were added simultaneously. Kinetic studies with human microsomes confirm the contribution of two different enzymes in the N-demethylation. The Km of 1A2 was similar to the high affinity Km in human liver microsomes, whereas the Km of 3A was similar to the low affinity Km in human liver microsomes. P-450 1A2 was apparently more efficient than 3A4 (lower Km and higher Vmax) but was expressed in much lower concentration. Human P-450s 1A2 and 3A4 expressed in yeast efficiently produced desmethylimipramine. These results suggest that P-450 1A2 and P-450 3A4 are the major enzymes involved in imipramine N-demethylation in human hepatic microsomes. Similar experiments were conducted using P-450 2D6, and they confirmed that P-450 2D6 catalyzes imipramine 2-hydroxylation. Interindividual variations in 3A4 hepatic content may explain the large variations in imipramine blood levels observed after uniform dosages and thus may explain the variations in clinical efficacy. Caution might be advised in the clinical use of tricyclic antidepressants when drugs are also administered that induce or inhibit P-450s 3A4 and 1A2.

Adult↗
PubMed1992

[VVI mode cardiac pacing: cause or risk factor of cerebral embolism?].

Epidemiological studies suggest that VVI pacing is associated with a higher risk of embolic complications than atrial or dual chamber pacing. However, no studies have been performed on pacemaker patients admitted to a neurological department with a cerebral embolism. The authors report the cases of 8 patients (6 men and 2 women) with an average age of 74 years and having the following characteristics: 1) a cerebral embolism, 2) a permanent cardiac pacemaker (7 VVI and 1 DDD mode). The average delay between implantation of the pacemaker and the neurological complication was 31 months. Cardiological investigations at the time of admission showed: a clinically evident cause of cardiac embolism in 3 cases (2 with VVI and 1 with DDD pacing); paroxysmal or permanent atrial fibrillation in 4 cases with VVI pacing at the time of the embolic event (in only one case at the time of implantation); various echocardiographic abnormalities in 6 of the 7 patients who underwent this examination, mainly left atrial dilatation (6/7), septal wall motion abnormalities in all related to ventricular pacing and unexplained left ventricular dilatation in 2 patients with VVI pacemakers. These results suggest that although the etiology of cerebral embolism was probably multifactorial in some patients, VVI packing probably a predisposing role, though not the only cause, and could be considered to be an embolic risk factor as suggested by previous epidemiological studies. These preliminary retrospective data should be interpreted cautiously taking into account the small population size. Prospective studies on pacemaker patients with cerebral embolism are required.

Aged↗
PubMed1992

[Cerebral infarction, placoid epitheliopathy and sarcoidosis].

We report a case of cerebral infarction in the basal territory of the left middle cerebral artery, associated with acute posterior multifocal placoid pigment epitheliopathy, most probably due to sarcoidosis. Neurological symptoms resolved spontaneously without sequelae. We discuss the relationship between acute posterior multifocal placoid pigment epitheliopathy, sarcoidosis and cerebral granulomatous angiitis.

Adult↗
PubMed1992

Anti-liver microsomes autoantibodies and dihydralazine-induced hepatitis: specificity of autoantibodies and inductive capacity of the drug.

Anti-liver microsomes (anti-LM) autoantibodies in patients with dihydralazine-induced hepatitis were found to react specifically with cytochrome P4501A2 (P4501A2) but not with P4501A1 expressed in yeast and bacteria. These results were confirmed by immunoinhibition of methoxyresorufin-O-demethylase activity (supported by the P4501A subfamily); anti-LM antibodies more strongly inhibited this activity in yeast expressing P4501A2 than in yeast expressing P4501A1. Anti-LM were shown to be specific to the disease; in three cases, these autoantibodies were present at high titers during disease, whereas the titers decreased upon recovery and became undetectable a few months after recovery. Thus, there exists a time-dependent relationship between the disease and the autoantibodies, which does not prove that the autoantibodies are causative of the hepatitis; they might only be a marker. The inductive capacity of dihydralazine toward P450 was also studied. In rats treated in vivo and in human hepatocytes treated in vitro with dihydralazine, a 2-fold increase in P4501A2- and P4501A-supported monooxygenase activities was found. The levels of the other P450 isoforms tested were unchanged during treatment, both in vivo in rats and in vitro in cultures of human hepatocytes. In human hepatocytes, dihydralazine produced a dose-dependent increase in the level of P4501A up to 0.1 mM; induction of P4501A was less strong at 0.2 mM and disappeared at 0.5 mM. The same treatment did not change the level of P4503A4, taken as control. The strong heterogeneity in the expression of P4501A enzymes in human liver and the capacity of these enzymes for induction by dihydralazine and by other compounds might be predisposing factors in this autoimmune disease.

Animals↗
PubMed1992

Characterization of human lung microsomal cytochrome P-450 1A1 and its role in the oxidation of chemical carcinogens.

Rat and human lung microsomal cytochrome P-450 (P-450) enzymes have been characterized with regard to their catalytic activities towards several xenobiotic chemicals, including procarcinogens, in different microsomal preparations. Rat lung microsomal P-450s were more active than the human P-450s in catalyzing most of the monooxygenation reactions. Human lung microsomal P-450 was solubilized and purified. Human lung microsomes contain approximately 10 pmol of P-450/mg of protein, on the basis of Fe2+.CO versus Fe2+ difference spectra of the eluates obtained from an octylamino-agarose column. The partially purified P-450 preparations from two human lung microsomal samples showed high activities for the conversion of both (+)- and (-)-isomers of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to genotoxic products. After DEAE-cellulose column chromatography, a partially purified P-450 fraction containing polypeptides of Mr 52,000 and 58,000 was obtained from the early fraction of the octylamino-agarose column eluate, and an electrophoretically homogeneous protein having a molecular weight of approximately 52,000 was recovered from a latter fraction. The amino-terminal amino acid sequences of the two peptides in the earlier fraction were determined; neither polypeptide appears to resemble any known P-450 protein. The protein from the latter octylamino-agarose fraction was immunoreactive with anti-rat P-450 1A2 and anti-human P-450 1A2 but not with antibodies raised against other P-450 enzymes or autoimmune antibodies that specifically recognize human P-450 1A2. A tryptic peptide was isolated from the preparation, and the amino acid sequence matched that of human P-450 1A1 perfectly (residues 31-48) but not that of human P-450 1A2. All of nine human lung microsomal samples examined contained proteins that were immunoreactive with rabbit anti-rat P-450 1A2 and catalyzed the activation of 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene. The activities could be inhibited by rabbit anti-rat P-450 1A2 and, to a lesser extent, by anti-rat P-450 1A1. The addition of 7,8-benzoflavone caused inhibition or stimulation, depending upon the particular human lung microsomal preparation. Thus, this work clearly shows that human lung microsomes contain at least two major P-450 enzymes; human P-450 1A1 is present in lungs and can actually catalyze the activation of environmental procarcinogens, including polycyclic aromatic hydrocarbons.

Animals↗
PubMed1992

[Infarcts in the region of the middle cerebral artery. Study of 501 cases in 484 patients].

We report a study of 501 infarcts in the middle cerebral artery (MCA) territory, in 484 patients. All cases had an appropriate low-density area on computed tomography. The basal (perforators) territory was involved in half the cases and the motor pathways either in the pre-rolandic area or in the internal capsule in 90%. In all locations, except for watershed infarcts, the main cause was cardiac embolism. Atrial fibrillation accounted for 59%, the two other main causes were myocardial infarction and paradoxical embolism. Atherosclerosis accounted for less than one third of the cases. Among 102 internal carotid artery occlusions less than one half were due to atherosclerosis, cardiac embolism and dissecting aneurysms accounted for 22% each. None of 34 MCA occlusions were due to atherosclerotic thrombotic occlusion. Transient ischemic attacks were recorded in 22% of the cases. Stroke-in-progression with a mean duration of 6-8 hours in hospital, was noted in nearly half the cases. In a small group of MCA infarcts paralysis began and predominated on the lower limb, fifteen contralateral old MCA infarcts were silent. Ten of these were on the right side. The 15 patients with silent infarcts were all right-handed.

Adolescent↗
PubMed1991

[Comparison between x-ray computed tomography and magnetic resonance imaging after transient ischemic accidents].

We studied 18 patients with transient ischemic accidents (TIA) and normal CT scan during the first 24 hours. MRI was performed 9 days later on average. MRI revealed abnormalities in 10 patients (56 p. 100), but only 5 of them (27 p. 100) had lesions corresponding to TIAs, and in every case these were in the carotid territory. In the 7 patients with clinical signs of TIA in the vertebro-basilar territory, MRI was always negative. In 5 patients (27 p. 100), MRI showed abnormalities that were unrelated to TIA. This study suggests that MRI is of limited value in detecting brain tissue abnormalities and is perhaps not more sensitive than CT in vertebro-basilar TIA. However, in view of the small number of patients these results must be interpreted with caution.

Humans↗
PubMed1991

[Thrombolytic agents in cerebral infarctions].

Thrombolytic agents are aimed at restoring arterial patency thus reducing the risk of cerebral infarction in case of arterial occlusion by blood thrombus or embolus. A review of data from the literature is presented, and the authors have tried to answer the following questions: 1) What are the probabilities of early mortality (first 30 days) and of morbidity due to untreated or medically (thrombolysis excluded) treated cerebral infarction? 2) What are the morbidity and mortality rates after systemic thrombolysis or selective intraarterial thrombolysis? 3) Are the results of thrombolysis affected by the site of arterial occlusion (carotid or vertebrobasilar system)? 4) Does thrombolysis increase the risk of cerebral haemorrhage? 5) Can thrombolysis be regarded as an effective treatment and, if so, in which cases? This study of systemic thrombolysis yielded a mean mortality rate of 22.2%, with satisfactory functional outcome in 58.2% of the survivors. The corresponding figures for selective intraarterial thrombolysis were 29.7% and 84.5% respectively. However when the arterial territories occluded were taken into account, they became 10.4% and 84.4% respectively in the carotid system and 61.5% and 85.00% in the vertebrobasilar system. Comparisons between the natural history of cerebral infarctions, as far as it is known, and the results of thrombolysis suggest that thrombolytic agents are: 1) probably justified by the selective intraarterial route when the occlusion lies in the carotid system; 2) not indicated by the systemic route with urokinase or streptokinase but trials with tPA are being performed. These conclusions, however, must be interpreted with caution as they rest on general data leaving out a number of factors that are often neglected in reports particularly the exact site of arterial occlusion, chiefly in the vertebrobasilar system. From 3 limited cohorts it was possible to evaluate at about 14% the mortality rate in thrombolysis for basilar artery occlusion. This figure, compared with the 70-80% estimate found in the literature for untreated occlusions, suggests that the selective intraarterial thrombolysis may perhaps be indicated also in basilar artery occlusions. It must be noted that selective intraarterial thrombolysis is still an exceptional treatment which requires sophisticated techniques, highly qualified neuroradiologists and prompt application i.e. emergency stroke units.

Cerebral Infarction↗
PubMed1990

Arterial pathology in cerebellar infarction.

We reviewed 88 pathologically proven cerebellar infarcts, examining the entire thoracocervical arterial system (including the spinal part of the vertebral artery, the intracranial arteries, and the heart) in all cases. For 50 infarcts, we found an arterial occlusion. The intracranial part of the vertebral artery was involved in 38 infarcts (76%), the basilar artery in 20 infarcts (40%), and a cerebellar artery in 12 infarcts (24%). Eight infarcts were due to bilateral distal vertebral artery occlusions. For the 50 infarcts, the cause of the occlusion was atherosclerosis in 28 (56%) and a cardiac embolism in 12 (24%). For the remaining 38 infarcts, we found no arterial occlusions on postmortem examination. Of these 38 infarcts, 26 (68%) were associated with a cardiac source of emboli. For the entire group of 88 infarcts, atherosclerosis was the cause in 31 (35%), while a cardiac embolism was proven or presumed in 38 (43%). Dissecting aneurysms, atherosclerotic artery-to-artery embolism, or hemodynamic mechanisms could have been responsible for a few infarcts. We conclude that cerebellar infarcts often arise from cardiogenic embolism.

Aged↗
PubMed1990

[Paradoxal cerebral embolism: role of patent oval foramen].

A patent foramen ovale (PFO) is present in 25-35% of people at all ages of life and its size tends to increase with age. It is now possible to detect PFO's by contrast echocardiography and it has been shown that there exists quite frequently a spontaneous transient right-to-left shunt during systole and, moreover, a right-to-left shunt during Valsalva maneuver and coughing. Acute or chronic pulmonary hypertension are also causes of shunt. Besides, a highly statistical correlation has been found between PFO's and strokes of uncertain or absent cause. From 1984 to 1990 the authors have collected 29 cases with 47 embolic cerebral events. Twenty-five cases with 30 embolic cerebral events and a neurological report have been found in the literature from 1930 to 1986. The analysis of these 77 cerebral embolic events is presented. All ages and both sexes are equally affected. Several symptoms and signs can suggest the diagnosis: onset of the neurological disorders during an activity implying a Valsalva maneuver; onset during a recognized phlebitis of the legs of pelvis or, more often, in a clinical setting suggesting the possibility of phlebitis without overt symptoms and signs: post-partum, post-operative conditions with prolonged bed rest; concomitant pulmonary and cerebral embolism. In the authors series of 227 cerebral emboli, such paradoxical emboli account for 12.8% of the cases ant it is likely that the condition is still underdiagnosed.

Adult↗