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1.
Hum Exp Toxicol ; 27(5): 367-72, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18715882

RESUMO

This study was performed to assess the influence of age, sex, smoking, and contraceptive use on CYP2A6 activity. In the metabolism of caffeine, the conversion of 1,7 dimethylxanthine (17X) to 1,7 dimethiylurate (17U) is catalyzed primarily by CYP2A6. CYP2A6 phenotype was determined by the urinary ratio 17U:17X in the interval of 4-5 h after caffeine intake in 179 healthy white Spaniards (102 women and 76 men). There were 99 non-smokers and 80 smokers. Among women, 26 were taking oral contraceptives. The age was the most important predictive factor of CYP2A6 activity (P < 0.001) with older subjects having higher activity. The influence of the gender was more modest (P = 0.07) with women exhibiting borderline increased values of the CYP2A6 marker than men. Tobacco smoking did not affect CYP2A6 activity. However, the CYP2A6 marker resulted to be strongly related to the use of oral contraceptives. The women users of oral contraceptives had higher values of CYP2A6 marker than both women not taking oral contraceptives and men (P < 0.001 in both comparisons). The results indicate that age, oral contraceptive use, and possibly gender should be controlled in epidemiological studies dealing with CYP2A6 activity and its relationship with xenobiotics exposure and genetic or pathological factor.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Anticoncepcionais Orais , Fumar , Adolescente , Adulto , Fatores Etários , Biomarcadores/urina , Cafeína/administração & dosagem , Citocromo P-450 CYP2A6 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Fatores Sexuais , Espanha , Teofilina/urina , Ácido Úrico/análogos & derivados , Ácido Úrico/urina
2.
Mol Biol Rep ; 35(3): 473-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17577681

RESUMO

The human multidrug resistance gene (MDR1) encodes for P-glycoprotein (P-gp) which is a transmembrane transporter protein that acts as an efflux pump for a number of lypophilic compounds. It plays a protective role for cells against DNA damage. The wobble C3435T polymorphism at exon 26 has been associated with different expression levels and activity. Differences in allele frequency of the C3435T polymorphism have been demonstrated between distinct ethnic groups. In our study we examined these polymorphisms in 433 healthy individuals. From these, 229 were Central American mestizos from Nicaragua (n = 117) and El Salvador (n = 112) to be compared with a group of 204 North Spaniards, with the aim of detecting potential genotypic differences between these populations. The genotypes were determined by PCR-RFLP. The frequencies of the C allele were very similar among Central Americans (0.53) and Spaniards (0.52), which is consistent with the ethnic origin of Central American individuals (Amerindians and European Caucasians). In comparison to other previously studied populations, the C allele frequency in Central Americans was significantly lower than that found in African populations and higher than that observed in the Indian and Southwest Asian populations. These data may be relevant for dose recommendation of P-gp substrate drugs and also for studies of allele disease association in the Central American population.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Polimorfismo Genético/genética , Alelos , América Central/etnologia , Citidina/genética , Genótipo , Humanos , Espanha/etnologia , Timidina/genética
3.
Cancer Epidemiol Biomarkers Prev ; 8(2): 159-66, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10067814

RESUMO

To choose a sensitive protocol to discriminate populations exposed and not exposed to inducers, five urinary metabolite ratios (MRs) [MR1 (17X + 17U)/137X, MR2 (5-acetylamino-6-formylamino-3-methyluracil [AFMU] + 1X + 1U)/17U, MR3 (17X/137X), MR4 (AFMU + 1X + 1U + 17X + 17U)/137X, and MR5 (AFMU + 1X + 1U)/17X] were calculated in 4-5 h and 0-24 h urine samples after caffeine intake. One hundred twenty-five healthy volunteers (59 nonsmokers and 66 smokers) were included in the study. All ratios showed a log-normal distribution. MR2 in the two time intervals was the only ratio nondependent on the urine flow. Differences between nonsmokers and smokers could be detected with all ratios at 4-5 h. However, only MR2 and, to a lesser extent, MR5 allowed the discrimination of higher cytochrome P450 1A2 (CYP1A2) activity in smokers in the 0-24 h sample. Although smokers had increased urinary mutagenicity in relation to nonsmokers, a significant association between MRs and urine mutagenicity was observed only with MR2 in the 4-5 h interval; this ratio/time schedule being that of higher association with tobacco consumption. The most flow-dependent ratios, MR1, MR3, and MR4, were closely correlated with each other at the two intervals. The flow dependency profile of each ratio may explain their different power to indicate both tobacco exposure and tobacco-derived mutagenicity. In conclusion, MR2 in the period of 4-5 h after caffeine intake seems preferable, especially at high urine flow rates.


Assuntos
Cafeína/urina , Estimulantes do Sistema Nervoso Central/urina , Citocromo P-450 CYP1A2/metabolismo , Mutagênicos/farmacologia , Fumar/metabolismo , Micção , Adolescente , Adulto , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Exposição Ambiental , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Reologia , Fumar/urina , Teofilina/urina , Fatores de Tempo , Uracila/análogos & derivados , Uracila/urina , Ácido Úrico/análogos & derivados , Ácido Úrico/urina , Xantinas/urina
4.
Mutat Res ; 334(2): 259-65, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7885380

RESUMO

The mutagenic potential of carbamazepine (CBZ) therapy has been studied in 37 patients undergoing long-term treatment with this drug. Of the total group, 23 patients suffered from epilepsy and 14 from trigeminal neuralgia. Thirty-one healty subjects served as controls. Six mutagenicity assays with different end-points were performed. The possible cytogenetic alterations were evaluated by analyzing sister-chromatid exchange frequencies (SCE), chromosome aberrations (CA), micronuclei (MN), proliferation indices (PRI), and mitotic indices. The Salmonella assay with and without microsomal activation served to measure urinary mutagenicity. The results show that CBZ leads to an increase in SCE (p < 0.01) and PRI (p < 0.05) but had no effect on the other cytogenetic parameters. CBZ was negative in the urine mutagenicity test. Plasma levels of total CBZ, free CBZ and CBZ-10,11-epoxide did not correlate with the cytogenetic alterations. Even though folic acid and gamma-glutamyltranspeptidase were significantly different in patients and controls, there was no significant association between these values and SCE or PRI. Patients with epilepsy and those with trigeminal neuralgia did not differ with respect to the end-points analyzed.


Assuntos
Carbamazepina/efeitos adversos , Epilepsia/tratamento farmacológico , Testes de Mutagenicidade/métodos , Neuralgia do Trigêmeo/tratamento farmacológico , Adolescente , Adulto , Idoso , Biotransformação , Carbamazepina/análogos & derivados , Carbamazepina/sangue , Carbamazepina/urina , Estudos de Casos e Controles , Divisão Celular/efeitos dos fármacos , Criança , Aberrações Cromossômicas , Feminino , Humanos , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Índice Mitótico/efeitos dos fármacos , Salmonella typhimurium/efeitos dos fármacos , Troca de Cromátide Irmã , Estatísticas não Paramétricas
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