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1.
Kidney Int ; 51(1): 288-93, 1997 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8995745

RESUMEN

Neutral endopeptidase (NEP) is a 94 kDa ectoenzyme of the proximal tubule brush border, physiologically released into the urine with apical membrane fragments. As proximal tubular atrophy was a histological hallmark of Chinese herbs nephropathy (CHN), this study firstly determined renal excretion of NEP in healthy control subjects (N = 31), in patients with CHN (N = 26) and in women having consumed Chinese herbs and whose renal function was normal but running the risk of developing CHN (N = 27). Another patient group consisted of female patients with glomerular diseases (N = 12). At the same time, measurements of urinary microproteins (Clara cell protein, retinol binding protein, beta 2-microglobulin and alpha 1-microglobulin) were performed, as indicators of tubular dysfunction. Cell damage was estimated by the excretion of N-acetyl-beta-D-glucosaminidase (NAG). In the control group, the physiological NEP enzymuria was 43.1 micrograms/24 hr (geometric mean). In CHN patients, levels of urinary NEP were significantly decreased in those with moderate renal failure (26.7 micrograms/24 hr; N = 21; P < 0.05) and almost abolished in end-stage renal failure patients (4.35 micrograms/24 hr; N = 5; P < 0.05). In patients at risk as well as in patients with glomerular diseases, urinary NEP levels were not statistically different from those observed in control subjects (40.68 micrograms/24 hr and 48.5 micrograms/24 hr, respectively). Several degrees of tubular dysfunction and injury were noted in patients groups, as attested by increased urinary microproteins and NAG excretions. Considering the data from control and CHN patients, NEP enzymuria positively correlated with individual creatinine clearance values (r = 0.76; P = 0.0001) and negatively correlated with urinary microproteins levels (r = -0.55; P = 0.00001). Finally, NEP was regularly quantitated in the urine of 6 CHN patients for a period ranging from six months to two years and in 19 patients at risk during two years, respectively. In the first group, renal function progressively deteriorated in 3 patients, leading them to renal replacement therapy after 38 to 115 weeks. Stable parameters were observed in the remaining 3 patients. A direct correlation between creatinine clearance and NEP excretion was found longitudinally in each case. In the second group, no significant change of urinary NEP levels was observed (45.9 micrograms/24 hr), in parallel with stable renal function. Taken together, these results indicate that, in CHN patients, NEP enzymuria provides a rapid and noninvasive determination of the degree of structural impairment affecting the proximal tubular population and further reflecting the severity of the renal disease. The interest of this urinary marker in monitoring the progression of other tubulointerstitial diseases remains to be assessed.


Asunto(s)
Medicamentos Herbarios Chinos/efectos adversos , Túbulos Renales Proximales/enzimología , Túbulos Renales Proximales/patología , Nefritis Intersticial/inducido químicamente , Neprilisina/orina , Adulto , Biomarcadores , Femenino , Glomerulonefritis/inducido químicamente , Glomerulonefritis/enzimología , Glomerulonefritis/patología , Humanos , Glomérulos Renales/patología , Túbulos Renales Proximales/efectos de los fármacos , Persona de Mediana Edad , Nefritis Intersticial/enzimología , Nefritis Intersticial/patología , Estudios Prospectivos
2.
Hum Exp Toxicol ; 15 Suppl 1: S10-9, 1996 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8882556

RESUMEN

Within the framework of an European Commission-funded project, groups of industrial workers exposed to heavy metals (cadmium, mercury and lead) or solvents were studied together with corresponding control groups. Eighty-one measurements were carried out on urine and serum samples and the scientific results together with individual questionnaire information were entered into a central database. Data obtained was assessed centrally and individually in subsidiary studies. The measurable contributions were assessed either singly or in combination, of smoking, gender, metal exposure and site, to nephrotoxicity. The potential value of each test as an indicator of nephrotoxicity was then assessed on the basis of sensitivity and specificity. A number of new tests including prostaglandins and for extracellular matrix components were investigated as well as established tests for renal damage and dysfunction. The data obtained from this comprehensive study emphasises the value of noninvasive biomarkers for the early detection of nephrotoxicity due to environmental toxins. The urinary profile varied with the type of environmental/occupational toxin. By careful selection of a small panel of markers they can be used to indicate the presence of renal damage, the principal region affected, and to monitor the progress of disease and damage. Biomarkers were also used to confirm and tentatively establish safe exposure levels to nephrotoxins.


Asunto(s)
Evaluación Preclínica de Medicamentos , Contaminantes Ambientales/toxicidad , Riñón/efectos de los fármacos , Biomarcadores , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Evaluación Preclínica de Medicamentos/tendencias , Humanos
3.
Kidney Int ; 48(5): 1571-6, 1995 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-8544416

RESUMEN

Urinary excretion of five low molecular weight proteins (LMWP) [beta 2-microglobulin (beta 2m), cystatin C (cyst C), Clara cell protein (CC16), retinol-binding protein (RBP) and alpha 1-microglobulin (alpha 1m)], albumin and N-acetyl-beta-D-glucosaminidase (NAG) were quantified in 16 patients who followed a weight reduction program which included Chinese herbs, which have been incriminated in the genesis of Chinese herbs nephropathy (CHN). An additional group of four patients transplanted for CHN were investigated. Urinary data were obtained for comparison purpose in five groups of proteinuric patients: two groups with normal serum creatinine (SCr) and glomerular albuminura [12 patients with diabetes mellitus and microalbuminuria (DN), 10 patients with primary nephrotic syndrome (NS)]; two groups with normal SCr and toxic nephropathy [6 patients with analgesic (AN), 9 patients with cadmium nephropathy (CdN)]; and one group of seven patients with glomerular diseases and increased SCr (GN). Patients were classified according to serum level S beta 2m to take into account the possibility of overflow proteinuria at S beta 2m > or = 5 mg/liter. Three patients (CHN0) with a S beta 2m < 5 mg/liter, had a normal urinary protein pattern including NAG and a normal S beta 2m. Eight patients (CHN1) with a S beta 2m < 5 mg/liter had various abnormalities of their urinary protein pattern. In four of them (CHN1a) only beta 2m, RBP and CC16 were increased while total proteinuria and SCr were normal. In the other four (CHN1b and c) albumin, cyst C, alpha 1m and NAG were also elevated, while total proteinuria and SCr were moderately raised. Five patients (CHN2) with a S beta 2m > or = 5 mg/liter had a markedly increased excretion of all LMWP, albumin and NAG (CHN1 vs. CHN2, P < 0.05) as well as a further increase in total proteinuria and SCr. The urinary LMWP/albumin concentration ratio was strikingly higher in CHN patients than in patients with glomerular albuminuria (CHN1 vs. DN and NS, P < 0.01) or moderate renal failure with elevated S beta 2m level (CHN2 vs. GN, P < 0.01), confirming the existence of a tubular proteinuria independent of glomerular albuminuria or overflow proteinuria. A similar proteinuria pattern was present in the two toxic nephropathies (CdN and AN). This pattern was no longer recognizable after transplantation. In conclusion, CHN exhibits various profiles of tubular proteinuria which are the hallmarks of the disease. This pattern is still detectable in patients with renal failure and/or glomerular albuminuria. It is identical to that observed in cadmium and analgesic nephropathies. It does not recur after transplantation. Its most sensitive and reliable marker is a raised urinary level of CC16 or RBP.


Asunto(s)
Medicamentos Herbarios Chinos/efectos adversos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/orina , Proteinuria/sangre , Uteroglobina , Adulto , Analgésicos/efectos adversos , Cadmio/efectos adversos , Femenino , Humanos , Enfermedades Renales/cirugía , Glomérulos Renales , Trasplante de Riñón , Masculino , Peso Molecular , Proteínas/química , Proteínas/metabolismo , Proteínas de Unión al Retinol/orina
4.
Environ Res ; 70(1): 62-9, 1995 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-8603660

RESUMEN

The production of thiobarbituric acid-reactive substances (TBA-RS) and ethane, two markers of the lipid peroxidation process, was evaluated in rat lung and liver microsomal membranes incubated in the presence of either ferrous ions or a mixture of ferric ions and ascorbate. Microsomal fractions isolated from lung tissue were more resistant than those isolated from the liver. Compared to Fe2+, the association of Fe3+/ascorbate seemed to be totally ineffective in stimulating peroxidation of lung microsomes. The fatty acid profile of lung and liver microsomal membranes could not be responsible for their different susceptibility to free radical degradation. The microsomal fraction isolated from lung showed a higher vitamin E concentration than the liver. The importance of vitamin E in protecting lung membranes was assessed by using lung and liver isolated from vitamin E-deficient and vitamin E-supplemented rats. For both lung and liver microsomal fractions an inverse relationship between vitamin E concentrations and the extent of lipid peroxidation was observed. However, although the vitamin E concentrations in lung and liver microsomes isolated from rats submitted to a vitamin E-deficient diet were not different, lung microsomes still exhibited a lower production of TBA-RS and ethane than liver. In addition to vitamin E, other factors must be involved to explain the resistance of lung microsomes to lipid peroxidation.


Asunto(s)
Hierro/farmacología , Peroxidación de Lípido/efectos de los fármacos , Pulmón/ultraestructura , Microsomas Hepáticos/fisiología , Microsomas/fisiología , Vitamina E/fisiología , Animales , Ácido Ascórbico/farmacología , Etano/análisis , Etano/metabolismo , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Peroxidación de Lípido/fisiología , Masculino , Microsomas/química , Microsomas/metabolismo , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Vitamina E/metabolismo
5.
Int Arch Occup Environ Health ; 67(2): 135-8, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-7672858

RESUMEN

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are progressive neurodegenerative disorders involving motor neurones. The aetiology of the non-familiar forms is still unknown but it has been suggested that long-term exposure to heavy metals such as lead and mercury may play a role in the pathogenesis of these diseases. In 53 patients suffering from ALS (n = 42) and SMA (n = 9) the oral administration of dimercaptosuccinic acid (DMSA, 20 mg/kg) did not result in a greater mobilization of lead and mercury from peripheral depots than in control subjects. Although it cannot be excluded that the amount of lead or mercury excreted after DMSA administration may not be a reflection of the amount accumulated in the motor neurons, this study does not provide support for the hypothesis that heavy metals play a significant role in the occurrence of motor neurone diseases.


Asunto(s)
Esclerosis Amiotrófica Lateral/inducido químicamente , Plomo/efectos adversos , Mercurio/efectos adversos , Atrofia Muscular Espinal/inducido químicamente , Succímero/uso terapéutico , Adulto , Anciano , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Estudios de Casos y Controles , Terapia por Quelación , Femenino , Humanos , Plomo/orina , Masculino , Mercurio/orina , Persona de Mediana Edad , Atrofia Muscular Espinal/tratamiento farmacológico
6.
Mutat Res ; 239(1): 17-27, 1990 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-2195331

RESUMEN

Cobalt metal and cobalt compounds are extensively used for the production of high-temperature alloys, diamond tools, cemented carbides and hard metals, for the production of various salts used in electroplating and as catalysts, drying agents in paints, additives in animal feeds and pigments. Cobalt oxides are used not only in the enameling industry and for pigments, but also in catalytic applications. There is no indication that cobalt metal and cobalt compounds constitute a health risk for the general population. Allergic reactions (asthma, contact dermatitis) can be induced by certain cobalt compounds. Interstitial fibrosis has also been observed in workers exposed to high concentrations of dust containing cobalt, tungsten, iron, etc., mainly in the cemented carbides and the diamond-polishing industries. Several experiments have demonstrated that single or repeated injections of cobalt metal powder or some forms of cobalt salt and cobalt oxide may give rise to injection site sarcoma in rats and in rabbits but the human health significance of such data is questionable. Intratracheal administration of a high dose of one type of cobalt oxide induces lung tumors in rats but not in hamsters. In the latter long-term inhalation of cobalt oxide (10 mg/m3) did not increase the incidence of lung cancer. The human data are too limited to assess the potential carcinogenic risk for workers. Co2+ interacts with protein and nucleic acid synthesis and displays only weak mutagenic activity in microorganisms. Some cobalt salts have been reported to enhance morphological transformation of Syrian hamster embryo cells. Cobalt chloride displays some limited mutagenic activity in yeast and some cobalt compounds are able to produce numerical and structural chromosome aberrations in plant cells. Cobalt and its salts appear to be devoid of mutagenic and clastogenic activity in mammalian cells. Cobaltous acetate and cobaltous chloride have not been found to be teratogenic in hamsters and rats respectively.


Asunto(s)
Carcinógenos Ambientales , Cobalto/toxicidad , Mutágenos , Neoplasias/etiología , Teratógenos , Animales , Cobalto/farmacocinética , Humanos , Neoplasias/inducido químicamente , Neoplasias/epidemiología , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/etiología
7.
Toxicol Appl Pharmacol ; 91(1): 65-74, 1987 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-3672518

RESUMEN

Previous studies have shown that several factors may influence the methylation of inorganic arsenic by rat liver in vitro (Buchet and Lauwerys, 1985). The present study attempts to assess the relevance of these observations in vivo. Like man, rat inactivates inorganic arsenic by methylation to monomethylarsonic (MMA) and dimethylarsinic (DMA) acids which are excreted in urine along with unchanged inorganic arsenic (Asi). The administration of S-adenosylmethionine alone or in association with reduced (GSH) or oxidized glutathione or acetylcysteine and the increase of hepatic GSH level by butylated hydroxytoluene pretreatment do not stimulate the urinary excretion of the methylated arsenic metabolites following a challenge dose of inorganic arsenic. Conversely a reduction of the hepatic GSH level by phorone pretreatment greatly modifies the metabolism of inorganic arsenic in vivo. A reduction exceeding 90% of the control value leads to a decreased urinary excretion of MMA and DMA and an increased urinary excretion of inorganic arsenic. This is also associated with an increased accumulation of inorganic arsenic in the liver. This suggests that a drastic reduction of GSH level in liver not only impairs the methylation of inorganic arsenic but also impairs its biliary excretion. When GSH depletion is less severe, the total amount of arsenic excreted in urine after a challenge dose of NaAsO2 is not significantly different from that found in unpretreated animals but the proportion of the three metabolic forms is different: MMA is reduced whereas Asi and DMA tend to increase. These changes resemble those found in patients with liver insufficiency (J.P. Buchet, A. Geubel, S. Pauwels, P. Mahieu, and R. Lauwerys (1984). The influence of liver disease on the methylation of arsenite in humans. Arch. Toxicol. 55, 151-154). Long-term pretreatment of rats with CCl4 slightly reduces the amount of MMA and DMA excreted in urine following a challenge dose of inorganic arsenic. This effect may result from a reduction of GSH transferase activity by CCl4. This study demonstrates the important role of liver GSH in the metabolism of inorganic arsenic in vivo.


Asunto(s)
Arsénico/metabolismo , Hígado/metabolismo , Animales , Arsénico/orina , Arsenicales/metabolismo , Arsenicales/orina , Ácido Cacodílico/metabolismo , Ácido Cacodílico/orina , Tetracloruro de Carbono/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Glutatión/metabolismo , Cetonas/farmacología , Metilación , Oxidación-Reducción , Ratas , Ratas Endogámicas , Selenio/farmacología
8.
Am J Ind Med ; 11(2): 177-87, 1987.
Artículo en Inglés | MEDLINE | ID: mdl-3493689

RESUMEN

We examined sensitive biochemical and immunological markers of kidney function and damage in 53 male oil refinery workers exposed to hydrocarbons and compared their results with those of a control group of 61 age-matched nonexposed males. The mean duration of employment of exposed males was 11 years. The current levels of exposure to a variety of aliphatic and aromatic hydrocarbons, as determined by personal monitoring, were well below the current threshold limit values. No difference was found in the urinary tubular parameters beta-N-acetyl-D-glucosaminidase, beta 2-microglobulin (beta 2-m) and retinol-binding protein. Similar serum beta 2-m levels indicated no impairment of the glomerular filtration rate in the exposed workers. The levels of circulating immune complexes were also identical in both groups. The mean albuminuria was slightly higher (p less than .005) in the exposed group in a quantitative assay but was not dipstick-detectable. The mean urinary excretion of a renal antigen was also higher (p less than .05) in the exposed group and correlated with the excretion of albumin. Finally, slightly higher titers of anti-laminin antibodies were found in five exposed employees, but this was not accompanied by an increased albuminuria. We conclude that chronic low-level hydrocarbon exposure in these refinery workers does not lead to clinically significant renal abnormalities. Nevertheless, some findings are consistent with the possible role of hydrocarbon exposure in the induction of renal disturbances.


Asunto(s)
Industria Química , Hidrocarburos/efectos adversos , Enfermedades Renales/inducido químicamente , Enfermedades Profesionales/inducido químicamente , Adulto , Albuminuria/etiología , Antígenos/orina , Estudios Transversales , Humanos , Hidrocarburos/análisis , Riñón/inmunología , Enfermedades Renales/inmunología , Enfermedades Renales/orina , Masculino , Persona de Mediana Edad , Enfermedades Profesionales/inmunología , Enfermedades Profesionales/orina , Petróleo
9.
J Appl Toxicol ; 6(5): 313-6, 1986 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-3772006

RESUMEN

Four groups of male rats were given the following oral treatment: control group (n = 20) deionized drinking water, Mn group (n = 20) deionized drinking water containing 56 ppm Mn2+ (1 mmol/l), Cd group (n = 10) deionized drinking water containing 112 ppm Cd2+ (1 mmol/l) and Cd + Mn group (n = 10) deionized drinking water containing 112 ppm Cd2+ and 56 ppm Mn2+. Half of each group was sacrificed after 4 weeks and the other half after 8 weeks of treatment. At each time interval, the mean levels of Mn in blood, in urine and in the various tissues did not differ between the control and Mn groups. Furthermore, comparable Mn levels were found after 4 and 8 weeks of treatment. Microscopical examination of the brain failed to reveal any overt morphological alteration in the Mn group. With respect to the control group, the Cd and Cd + Mn groups exhibited increased levels of Cd in blood, urine, liver, whole kidney, kidney cortex and in brain (cortex, cerebellum, basal ganglia), but the Cd + Mn groups showed invariably lower levels than the Cd group after 4 weeks as well as after 8 weeks. These results suggest that the rate of gastrointestinal absorption of Cd is decreased by supplementation of the drinking water with a 'non-toxic' dose of Mn2+.


Asunto(s)
Cadmio/metabolismo , Absorción Intestinal/efectos de los fármacos , Manganeso/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Masculino , Manganeso/metabolismo , Ratas , Ratas Endogámicas , Distribución Tisular
10.
J Occup Med ; 25(9): 668-78, 1983 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-6631566

RESUMEN

A single-blind study was performed on male workers from a primary lead smelter to determine whether a daily oral supplement of vitamin C (1 g vitamin C orally once a day, five times a week for 20 weeks) or zinc (60 mg zinc as zinc gluconate once a day, five times a week for eight weeks) influences the absorption of and the biological (hematological and renal) response to lead. The vitamin C and the zinc study groups comprised 39 and 11 workers, respectively. Their blood levels of lead at the start of the experiment ranged from 28.9 to 76.4 micrograms/100 ml. A matched control group receiving a placebo was followed simultaneously. The results demonstrate that, in workers whose exposure to inorganic lead is moderate and who do not suffer from nutritional deficiencies, oral supplementation of vitamin C or zinc does not influence the metabolism and biological action of lead.


Asunto(s)
Ácido Ascórbico/administración & dosificación , Gluconatos/administración & dosificación , Plomo/metabolismo , Enfermedades Profesionales/metabolismo , Absorción , Administración Oral , Adulto , Ácido Ascórbico/farmacología , Gluconatos/farmacología , Humanos , Plomo/sangre , Plomo/orina , Masculino , Persona de Mediana Edad
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