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1.
Ann Intern Med ; 158(6): 469-77, 2013 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-23552405

RESUMO

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.


Assuntos
Ácidos Aristolóquicos/efeitos adversos , Nefropatias/induzido quimicamente , Preparações de Plantas/efeitos adversos , Nefropatia dos Bálcãs/induzido quimicamente , Nefropatia dos Bálcãs/diagnóstico , Nefropatia dos Bálcãs/epidemiologia , Nefropatia dos Bálcãs/terapia , Humanos , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/fisiopatologia , Nefropatias/terapia , Fatores de Risco , Neoplasias Urológicas/induzido quimicamente , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/epidemiologia , Neoplasias Urológicas/fisiopatologia , Neoplasias Urológicas/terapia
2.
Chem Res Toxicol ; 24(10): 1710-9, 2011 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-21932800

RESUMO

Exposure to aristolochic acid I (AAI) is associated with aristolochic acid nephropathy, Balkan endemic nephropathy, and urothelial cancer. Individual differences in xenobiotic-metabolizing enzyme activities are likely to be a reason for interindividual susceptibility to AA-induced disease. We evaluated the reductive activation and oxidative detoxication of AAI by cytochrome P450 (P450) 1A1 and 1A2 using the Cyp1a1(-/-) and Cyp1a2(-/-) single-knockout and Cyp1a1/1a2(-/-) double-knockout mouse lines. Incubations with hepatic microsomes were also carried out in vitro. P450 1A1 and 1A2 were found to (i) activate AAI to form DNA adducts and (ii) detoxicate it to 8-hydroxyaristolochic acid I (AAIa). AAI-DNA adduct formation was significantly higher in all tissues of Cyp1a1/1a2(-/-) than Cyp1a(+/+) wild-type (WT) mice. AAI-DNA adduct levels were elevated only in selected tissues from Cyp1a1(-/-) versus Cyp1a2(-/-) mice, compared with those in WT mice. In hepatic microsomes, those from WT as well as Cyp1a1(-/-) and Cyp1a2(-/-) mice were able to detoxicate AAI to AAIa, whereas Cyp1a1/1a2(-/-) microsomes were less effective in catalyzing this reaction, confirming that both mouse P450 1A1 and 1A2 are both involved in AAI detoxication. Under hypoxic conditions, mouse P450 1A1 and 1A2 were capable of reducing AAI to form DNA adducts in hepatic microsomes; the major roles of P450 1A1 and 1A2 in AAI-DNA adduct formation were further confirmed using selective inhibitors. Our results suggest that, in addition to P450 1A1 and 1A2 expression levels in liver, in vivo oxygen concentration in specific tissues might affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity.


Assuntos
Ácidos Aristolóquicos/farmacocinética , Carcinógenos/farmacocinética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Animais , Ácidos Aristolóquicos/urina , Nefropatia dos Bálcãs/enzimologia , Biotransformação , Citocromo P-450 CYP1A1/deficiência , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/deficiência , Citocromo P-450 CYP1A2/genética , Adutos de DNA , Suscetibilidade a Doenças , Feminino , Rim/enzimologia , Fígado/enzimologia , Pulmão/enzimologia , Camundongos , Camundongos Knockout , Microssomos/enzimologia , Neoplasias Urológicas/enzimologia
3.
Am J Kidney Dis ; 45(2): 407-10, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15685520

RESUMO

The authors report a case of unexplained nephropathy 2 months after ingestion of Herba Aristolochia Mollissemae in a patient with long-standing Crohn's disease and recently diagnosed carcinoma of the colon. It presented as a relentlessly progressing hypocellular interstitial nephritis 5 months after cessation of an earlier course of mesalazine. The patient finally had end-stage renal failure 12 months after taking herbs and required hemodialysis. Aristolochic acid (AA) was detected in the herbal sample of Herba Aristolochia Mollissemae by high-performance liquid chromatography-diode array detection and electrospray ionization-tandem mass spectrometry. Specific AA-DNA adducts were detected in the renal biopsy by 32 P-postlabelling analysis. Transitional cell carcinoma was diagnosed 5 months after herb ingestion. It was found that the originally prescribed nonnephrotoxic herb had been substituted by AA-containing Herba Aristolochia Mollissemae at the wholesaler level. Although AA-associated nephropathy could not be proved conclusively, the current case contributed to the withdrawal of the AA-related herbs by the local health authority in Hong Kong. Physicians should be on the alert for herbal nephrotoxicity by possible replacement of nontoxic herbs by nephrotoxic herbs.


Assuntos
Aristolochiaceae/metabolismo , Aristolochiaceae/intoxicação , Nefrite/induzido quimicamente , Ácidos Aristolóquicos/análise , Ácidos Aristolóquicos/intoxicação , Humanos , Rim/química , Rim/patologia , Masculino , Pessoa de Meia-Idade , Preparações de Plantas/metabolismo , Preparações de Plantas/intoxicação
4.
Arch Toxicol ; 77(4): 218-26, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12698237

RESUMO

Chinese-herb nephropathy (CHN) is a progressive renal interstitial fibrosis initially reported after concomitant intake of an anorexigen, (dex)fenfluramine, and a Chinese herb ( Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acid (AA). We thus tested the possible enhancing effect of the active enantiomer dexfenfluramine (DXF) on AA nephrotoxicity in a rat model for CHN. Groups of 12 salt-depleted male Wistar rats received daily subcutaneous injections of 7 mg/kg body weight DXF (DXF group), 7 mg/kg body weight AA (AA group), a combination of the same doses of AA and DXF (AA+DXF group), or vehicle (control group) for up to 35 days. Six animals per group were killed on day 10 and the remaining six on day 35. Renal function was evaluated by determining serum creatinine and urinary leucine aminopeptidase activity. Histological evaluation of kidney samples was performed and tubulointerstitial injuries were semiquantified. The DXF group did not differ from controls for any parameter. Similarly elevated serum creatinine levels, decreased leucine aminopeptidase enzymuria, and renal lesions were observed in the AA and the AA+DXF groups after both 10 and 35 days. The formation of specific AA-DNA adducts in liver and renal tissue samples was assessed by the (32)P-postlabelling method. Specific AA-DNA adduct levels were significantly increased in kidney tissues from AA+DXF rats compared with AA rats. These functional and histological data suggest that DXF does not enhance AA nephrotoxicity in a rat model for CHN. Further investigations are needed to clarify the mechanism by which DXF may enhance AA-DNA adduct formation.


Assuntos
Ácidos Aristolóquicos/toxicidade , Dexfenfluramina/toxicidade , Medicamentos de Ervas Chinesas/toxicidade , Mutagênicos/toxicidade , Nefrite Intersticial/patologia , Agonistas do Receptor de Serotonina/toxicidade , Animais , Ácidos Aristolóquicos/administração & dosagem , Ácidos Aristolóquicos/metabolismo , Autorradiografia , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Creatinina/urina , Adutos de DNA/análise , Adutos de DNA/efeitos dos fármacos , Dexfenfluramina/administração & dosagem , Modelos Animais de Doenças , Sinergismo Farmacológico , Fibrose/induzido quimicamente , Fibrose/metabolismo , Fibrose/patologia , Injeções Subcutâneas , Rim/química , Rim/efeitos dos fármacos , Fígado/química , Fígado/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Masculino , Mutagênicos/administração & dosagem , Mutagênicos/metabolismo , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/metabolismo , Radioisótopos de Fósforo/metabolismo , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/administração & dosagem
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