RESUMO
Hyperbilirubinemia in patients with sickle cell anemia (SCA) as a result of enhanced erythrocyte destruction, lead to cholelithiasis development in a subset of patients. Evidence suggests that hyperbilirubinemia may be related to genetic variations, such as the UGT1A1 gene promoter polymorphism, which causes Gilbert syndrome (GS). Here, we aimed to determine the frequencies of UGT1A1 promoter alleles, alpha thalassemia, and ßS haplotypes and analyze their association with cholelithiasis and bilirubin levels. The UGT1A1 alleles, -3.7 kb alpha thalassemia deletion and ßS haplotypes were determined using DNA sequencing and PCR-based assays in 913 patients with SCA. The mean of total and unconjugated bilirubin and the frequency of cholelithiasis in GS patients were higher when compared to those without this condition, regardless of age (P < 0.05). Cumulative analysis demonstrated an early age-at-onset for cholelithiasis in GS genotypes (P < 0.05). Low fetal hemoglobin (HbF) levels and normal alpha thalassemia genotype were related to cholelithiasis development (P > 0.05). However, not cholelithiasis but total and unconjugated bilirubin levels were associated with ßS haplotype. These findings confirm in a large cohort that the UGT1A1 polymorphism influences cholelithiasis and hyperbilirubinemia in SCA. HbF and alpha thalassemia also appear as modulators for cholelithiasis risk.
Assuntos
Anemia Falciforme/sangue , Bilirrubina/sangue , Colelitíase/etiologia , Doença de Gilbert/sangue , Glucuronosiltransferase/fisiologia , Regiões Promotoras Genéticas/genética , Talassemia alfa/sangue , Adolescente , Adulto , Idoso , Alelos , Anemia Falciforme/complicações , Anemia Falciforme/enzimologia , Anemia Falciforme/genética , Criança , Pré-Escolar , Colelitíase/sangue , Colelitíase/genética , Feminino , Hemoglobina Fetal/análise , Genótipo , Doença de Gilbert/enzimologia , Doença de Gilbert/genética , Glucuronosiltransferase/genética , Haplótipos/genética , Hemólise , Humanos , Hiperbilirrubinemia/enzimologia , Hiperbilirrubinemia/etiologia , Hiperbilirrubinemia/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Talassemia alfa/complicações , Talassemia alfa/enzimologia , Talassemia alfa/genéticaRESUMO
Although continuous researches are going on for the discovery of new chemotherapeutic agents, resistance to these anticancer agents has made it really difficult to reach the fruitful results. There are many causes for this resistance that are being studied by the researchers across the world, but still, success is far because there are several factors that are going along unattended or have been studied less. Drug-metabolizing enzymes (DMEs) are one of these factors, on which less study has been conducted. DMEs include Phase I and Phase II enzymes. Cytochrome P450s (CYPs) are major Phase I enzymes while glutathione-S-transferases (GSTs), UDP-glucuronosyltransferases (UGTs), dihydropyrimidine dehydrogenases are the major enzymes belonging to the Phase II enzymes. These enzymes play an important role in detoxification of the xenobiotics as well as the metabolism of drugs, depending upon the tissue in which they are expressed. When present in tumorous tissues, they cause resistance by metabolizing the drugs and rendering them inactive. In this review, the role of these various enzymes in anticancer drug metabolism and the possibilities for overcoming the resistance have been discussed.
Assuntos
Antineoplásicos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Catálise , Sistema Enzimático do Citocromo P-450/fisiologia , Di-Hidrouracila Desidrogenase (NADP)/fisiologia , Glucuronosiltransferase/fisiologia , Glutationa Transferase/fisiologia , Humanos , Inativação MetabólicaRESUMO
La glucuronoconjugación es un proceso de gran importancia en el metabolismo de xenobióticos y sustancias endógenas, facilitando su excreción por parte del organismo. Durante mucho tiempo ha sido aceptado que los metabolitos derivados de esta vía no poseían carácter activo o reactivo. Sin embargo, en los últimos años han surgido evidencias que ponen en duda aquella creencia, con especial referencia a los acilglucurónidos de los ácidos aril 2-propiónicos, cuya inestabilidad in vivo bajo condiciones fisiológicas ha demostrado tener implicancias inmunotoxicológicas potenciales a través de su unión irreversible a las proteínas (aductos). Esta revisión considera los aspectos que han modificado la percepción de la glucuronoconjugación como una vía sin importancia toxicológica y clínica para el organismo. Por lo tanto, la pregunta que debería ser contestada podría ser: es la glucuronoconjugación una vía de producción de sustancias tóxicas tanto como un mecanismo de detoxificación?
Assuntos
Humanos , Animais , Ratos , Gatos , Camundongos , Ácidos Carboxílicos/efeitos adversos , Propionatos/metabolismo , Fatores Etários , Anti-Inflamatórios não Esteroides/metabolismo , Biotransformação , Glucuronatos/metabolismo , Glucuronidase/fisiologia , Glucuronosiltransferase/metabolismo , Glucuronosiltransferase/fisiologia , Uridina Difosfato Ácido Glucurônico/fisiologia , Reações Biológicas , Inativação Metabólica/fisiologia , Flurbiprofeno/metabolismo , Isomerismo , Cetoprofeno/metabolismo , Naproxeno/metabolismo , Coelhos , Sexo , Tolmetino/metabolismo , Triglicerídeos , Xenobióticos/metabolismoRESUMO
La glucuronoconjugación es un proceso de gran importancia en el metabolismo de xenobióticos y sustancias endógenas, facilitando su excreción por parte del organismo. Durante mucho tiempo ha sido aceptado que los metabolitos derivados de esta vía no poseían carácter activo o reactivo. Sin embargo, en los últimos años han surgido evidencias que ponen en duda aquella creencia, con especial referencia a los acilglucurónidos de los ácidos aril 2-propiónicos, cuya inestabilidad in vivo bajo condiciones fisiológicas ha demostrado tener implicancias inmunotoxicológicas potenciales a través de su unión irreversible a las proteínas (aductos). Esta revisión considera los aspectos que han modificado la percepción de la glucuronoconjugación como una vía sin importancia toxicológica y clínica para el organismo. Por lo tanto, la pregunta que debería ser contestada podría ser: es la glucuronoconjugación una vía de producción de sustancias tóxicas tanto como un mecanismo de detoxificación? (AU)
Assuntos
Humanos , Animais , Ratos , Gatos , Camundongos , Propionatos/metabolismo , Glucuronosiltransferase/fisiologia , Uridina Difosfato Ácido Glucurônico/fisiologia , /metabolismo , Glucuronatos/metabolismo , Glucuronidase/fisiologia , Ácidos Carboxílicos/efeitos adversos , Biotransformação/efeitos dos fármacos , Glucuronosiltransferase/metabolismo , Fatores Etários , Sexo , Xenobióticos/metabolismo , Triglicerídeos , Coelhos , Naproxeno/metabolismo , Cetoprofeno/metabolismo , Flurbiprofeno/metabolismo , Tolmetino/metabolismo , Isomerismo , Inativação Metabólica/fisiologia , Reações BiológicasRESUMO
To evaluate whether a temporary hepatic insufficiency may affect intestinal glucuronidation, we determined UDP-glucuronosyltransferase activity towards bilirubin and p-nitrophenol in rat jejunum and liver after partial hepatectomy. Enzyme assays were performed in native, and in UDP-N-acetylglucosamine- or palmitoyl lysophosphatidylcholine-activated microsomes at different times post-hepatectomy. Content of enzyme was analyzed by Western blot. Microsomal cholesterol/phospholipid ratio, phospholipid and total fatty acid classes were also determined to evaluate the possible influence on enzyme activity. The results show that while hepatic microsomes exhibited no change in UDP-glucuronosyltransferase activity (for both substrates) with respect to shams at any time of study, intestinal activities increased significantly 48 h after surgery, returning to sham values 96-h post-hepatectomy. Western blotting confirmed the increase (about 50% for both substrates 48-h post-hepatectomy) in intestinal UDP-glucuronosyltransferase activity. No variations were observed in hepatic and intestinal microsomal lipid composition in agreement with the absence of modification in the percent of activation by palmitoyl lysophosphatidylcholine. In conclusion, jejunum but not liver, was able to produce a compensatory increase in conjugation capacity during a transitory loss of hepatic mass. The phenomenon is associated to a modification in the amount of UDP-glucuronosyltransferase, rather than to changes in the characteristics of the enzyme environment.