摘要:

Abstract:Chemotaxis and niroblue tetrazolium reduction were measured in peripheral blood neutrophils of workers occupationally exposed to lead. These two neutrophil functions were significantly reduced, as compared to controls, even in those workers with blood lead levels and urinary delta‐aminolevulinic acid (ALA‐U) concentrations below the currently accepted biological limit values of 60 μ/dl and 6 mg/1, respectively. The immunosuppressive effects of relatively low level lead absorption suggests that immune dysfunction may be a sensitive indicator of lead expo

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00293.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Interindividual variation of the metabolism of prednisolone and of the susceptibility to glucocorticoids might be possible factors contributing to the development of osteonecrosis after renal allotransplantation. As this aspect has not been properly investigated previously, we compared, in the present study, the metabolism of total and free prednisolone in 6 renal allotransplanted patients who subsequently developed osteonecrosis of the femoral head and the metabolism of 6 matched controls, who did not develop osteonecrosis. There was no difference in age, bodyweight, total serum protein or albumin, or in liver or renal function. The baseline cortisol was 54 ± 23 pg in patients with necrosis, and 102 ± 53 μg/1 in patients without necrosis (n.s.). Likewise there was no difference in the peak concentration of prednisolone (420 ± 43 vs. 394 ± 42 μg/1, n.s.), the bioavailability (0.57 ± 0.09 vs. 0.61 ± 0.05, n.s.) or in the apparent volume of distribution at steady state (Vdss, 0.37 ± 0.09 vs. 0.37 ± 0.04 1/kg, n.s.). The clearance of prednisolone in patients with osteonecrosis was 33% lower (0.79 ± 0.11 vs. 1.18 ± 0.13 ml/min./kg b.wt., P<0.05) and t1/2was correspondingly 33% longer (246 ± 18 min. vs. 184 ± 15 min., P<0.05) than in patients without osteonecrosis. However, there was no difference in the apparent volume of distribution of free prednisolone (2.07 ± 0.36 vs. 1.69 ± 0.28 1/kg, n.s.), in the t½(152 ± 30 vs. 107 ± 20 min., n.s.), or in the clearance (7.33 ± 2.12 vs. 7.82 ± 1.18 ml/min./kg) between the two groups. It is, therefore, concluded, that in spite of the reduced metabolic clearance of total prednisolone, the unchanged pharmacokinetics of free prednisolone indicate, that the development of steroid induced osteonecrosis of the femoral head may not be explained by altered pharmacokinetics of prednisone and prednisolo

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00294.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:As an extension of a previous study on the metabolism of14C‐1‐naphthol (1‐N) by the isolated guinea pig mucosa (Sund&Lauterbach 1986), the isomeric compound 2‐naphthol (2‐N, 50‐130 nmol/ml) has now been examined.14C‐Labelled drug was added to the luminal or contraluminal fluid bathing the two sides of jejunal or colonic mucosal sheets in a symmetrical set up. After aerobic incubation for 45 min. at 37°, the fluid compartments and the tissue were analysed for parent drug and metabolites. Like I‐N 2‐N was transformed into its sulphate and glucuronide. In the jejunum, 2‐N was more extensively sulphated than 1‐N, whereas in the colon the metabolite profiles (sulphate: glucuronide ratio) of the two isomers were similar. Generally, the metabolism rate of 2‐N, its metabolite profile and metabolite transport pattern (lumen: blood distribution ratio) as well as the tissue accumulation of parent drug and metabolites, depended on the side of drug administration and on the tissue studied. Thus, changing the drug administration had a pronounced impact on the jejunal metabolism and transport, but caused only minor effects in the colon. In summary, this study emphasizes that drug metabolism and metabolite transport differ in the small and large intestine. The data further support the hypothesis that jejunal drug metabolism takes place in two compartments, of which the most active one is accessible from the lumen side and the other from the blood side. The possibility that colonic drug metabolism may also involve compartmentation should be considered although the present study provided very

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00295.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Perfluorooctane sulfonic acid is almost as potent as perfluorooctanoic acid in causing increases in peroxisomal fatty acid β‐oxidation, peroxisomal catalase activity, Ω‐hydroxylation of lauric acid, cytosolic epoxide hydrolase activity and cytosolic DT‐diaphorase activity. Octane sulfonic acid was ineffective at doses used for perfluorooctane sulfonic acid and perfluorooctanoic acid. The results support the theory of co‐regulation of these parameters and peroxisome proliferation. The fact that perfluorooctane sulfonic acid causes peroxisome proliferation challenges the hypothesis that the first step in this process is formation of a thioester between the proliferator (the carboxylic group) and c

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00296.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Recent studies suggest thatin vivoprocainamide oxidation underlies induction of autoimmunity by this drug. Since drug metabolism may be accompanied by generation of reactive oxygen species, plasma and liver thiobarbituric acid reacting substances (TBARS), activity of erythrocyte and liver superoxide dismutase, catalase, selenium‐dependent glutathione peroxidase (Se‐GPX), and plasma antioxidant activity in procainamide treated rats were evaluated. Procainamide administration increased liver lipid peroxide levels, intensified the activity of liver catalase and erythrocyte superoxide dismutase, as well as plasma antioxidant activity. The remaining biochemical parameters in the treated rats were within control values, except for the decreased erythrocyte catalase activity. We conclude, that the increased activity of free radicals observed in the treated rats could contribute to the development of procainamide induced side effe

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00297.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Recirculating, retrograde heart perfusion according to the Langendorff method was used in an attempt to further elucidate the cardiotoxicity of methyl‐2‐tetradecylglycidate (McNeil 3716, MTG) and the excentric hypertrophy elicited by the compound. In subchronic experiments female rats were exposed to MTG 2 × 10 mg/kg and 2 × 25 mg/kg per day for 4 weeks. At various times hearts were perfusedex vivofor up to 2 hr with either 5 mmolar glucose or 0.5 mmolar palmitate as substrate. Substrate uptake (glucose or palmitate) and enzyme release (LDH‐lactic dehydrogenase or CPK‐creatinphosphate kinase) were assessed during perfusion. Biochemical analysis (ATP, ADP, AMP, c‐AMP, CP, creatine, pyruvate, lactate, glucose‐6‐phosphate, glycogen, phospholipids, triglycerides and non‐esterified fatty acids) were done in hearts before (drug effect) and after perfusion (stress of perfusion). Besides changes in energy metabolism and high‐energy phosphate production, as observed in previous experiments (Bachmannet al.1984) massive changes were seen in energy reserves in heart tissue (ATP, CP, glycogen, phospholipids and triglycerides). As expected, MTG led to significant increases also in non‐esterified fatty ac

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00298.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Pulmonary coumarin 7‐hydroxylase, testosterone hydroxylase and other P450‐mediated activities were compared in the mouse and rat. Coumarin 7‐hydroxylase activity was 20 pmol/mg/min. in mouse and 4 pmol/mg/min. in rat lung microsomes. Liver values were 180 (mouse) and 1 (rat) pmol/mg/min. Kmvalues of rat and mouse lung coumarin 7‐hydroxylase were about 1 μM whereas the rat liver Kmvalue was>100 μM. Phenobarbital and 3‐methylcholanthrene did not affect rat lung (or liver) coumarin 7‐hydroxylase activity. Anti‐Cyp2a‐5 antibody effectively inhibited mouse and rat lung coumarin 7‐hydroxylase and testosterone 15α‐hydroxylations but failed to block these activities in the rat liver. In immunoblot analysis anti‐Cyp2a‐5 antibody recognized the 50‐kDa Cyp2a‐4/5 protein in mouse lung microsomes. A P450 protein co‐migrating with Cyp2a‐5 was also detected in rat lung microsomes.Cyp2a‐5cDNA probe hybridized with a 1.8‐kb mRNA species in rat lung RNA fraction. The hybridization signal was not increased by 3‐methylcholanthrene or phenobarbital. These data suggest that the mouse lung expresses Cyp2a‐5 which differs from the liver enzyme only in its regulation and that the rat lung contains a P450 isoform(s) belonging to the 2A subfamily which may be orthologous with the mouse Cyp2a‐415 catalyzing coumarin 7‐hydroxylase and testosterone 15a‐hydroxylase activities. The recently reported rat lung CYP2A3 (Kimuraet al.)gene product is a candidate for the observed

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00299.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Debrisoquine and S‐mephenytoin hydroxylation polymorphisms were studied in 156 unrelated native Estonians. The hydroxylation phenotypes were assessed by coadministration of mephenytoin with debrisoquine or dextromethorphan. The frequency of the poor metaboliser phenotype of debrisoquine/dextromethorphan was 4.5% (95% confidence interval 1.2‐7.8%), and that of mephenytoin was 3.9% (95% confidence interval 0.9‐6.9%) among Estonians, which is very similar to what has been reported in other Caucasian popula

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00300.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Pretreatment of mice with 5‐fluoromethylornithine (SFMOrn), a selective inactivator of ornithine aminotransferase, diminishes the accumulation of ammonia in the brain after administration of ammonium acetate, and antagonizes ammonia‐induced fatal tonic extensor convulsions. In about 50% of the treated animals the loss of the righting reflex and coma is prevented. Presumably these effects are based on the enhancement of urea formation by the increased liver ornithine concentrations. However, since brain ornithine concentrations are greatly enhanced by SFMOrn, it is not excluded that ornithine has direct effects on cellular events involved in ammonia‐induced seizure generation, even though 5FMOrn had no anticonvulsant properties in a series of established animal seizure models, including N‐methyl‐D,L‐aspartate‐induced convulsions. NMDA receptor antagonists are capable of preventing death, but do not protect against the generation of coma and tonic extensor convulsions in ammonium acetate intoxicated mice. Since no evidence was found for ammonia‐induced glutamate release from rat hippocampus, there is no convincing evidence for the idea that the tonic convulsions are mediated by NMDA receptors. L‐Methionine‐D,L‐sulfoximine (MSO)‐induced seizures can be partially antagonized by pretreatment with 5FMOrn. However, the effect is considerably smaller than against ammonia‐induced convulsions, although at the time of seizure onset brain ammonia levels of MSO‐intoxicated mice were lower than in the animals receiving ammonium acetate. This suggests that MSO‐convulsions are not entirely due to the elevation of brain ammonia concentrations, even though MSO administration mimicks effects of ammonia on cortical inhibitory neuronal interactions. Based on its potency and duration of action, administration of SFMOrn recommends itself as a highly effective method to antago

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00301.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Sprague‐Dawley rats were fed either a standard diet with 0.9/0.7% Ca/P or a semisynthetic low‐calcium diet with 0.5/0.4% Ca/P and treated orally for 28 days with 1α‐hydroxycholecalciferon [lα(OH)D3], a synthetic analogue of the physiologically active form of vitamin D3, lα,25‐dihydroxycholecalciferol [1α,25(OH)2D3], at dose levels of 0.2 and 2.0 μg/kg/day. The high dose caused severe hypercalcaemia with retarded growth, nephrosis, and structural bone changes in rats fed the standard diet. The same dose caused only slight hypercalcaemia without growth retardation or bone changes, and only minimally affected the kidneys in rats fed the low‐calcium diet. Hypercalcaemia with less pronounced pathological changes was found in the standard diet low‐dose rats, whereas no hypercalcemia or pathological changes were found in the low‐calcium diet low‐dose group. The rats fed the low‐calcium diet tolerated 1α(OH)D3at dose levels up to 10 times higher than rats on the standard diet. The use of diets low in calcium and low in phosphorus will thus allow the administration of higher dosages of vitamin D compounds without causing hypercalcaemia. This may permit a better evaluation of the pharmacologic and toxic effects not directly associated with the calcium‐regulating properties of vitamin D

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb00302.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY