RESUMO
Patients with Gilbert syndrome have an impaired function of the enzyme UGT1A1, responsible for the degradation of 4-OH-estrogens. These elements are produced by the degradation of estrogens and are well-known carcinogens. In theory, patients with Gilbert syndrome accumulate 4-OH-estrogens and, therefore, might have a higher risk for breast cancer, especially when exposed to higher levels of estrogens. If this theory is true, a new risk group for breast cancer would be described, producing new insights in breast carcinogenesis.
Assuntos
Neoplasias da Mama/etiologia , Estrogênios/metabolismo , Doença de Gilbert/complicações , Glucuronosiltransferase/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Doença de Gilbert/genética , Doença de Gilbert/metabolismo , Glucuronosiltransferase/genética , Humanos , Modelos Biológicos , Polimorfismo Genético/genética , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones. METHODS: Loci that were identified in a meta-analysis to attain a genome-wide significance level of a P value less than 1.0×10(-7) (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German choleystecomized individuals and 1121 controls and was replicated in 210 cases and 496 controls from South America. RESULTS: By using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1; P = .003), rs4149056 (SLCO1B1; P = .003), and rs4149000 (SLCO1A2; P = .015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model. UGT1A1 (rs6742078; P = .018) was associated with overall gallstone risk. In a sex-stratified analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P = 2.1×10(-7); odds ratio(recessive), 2.34; P(women) = .47). The sex-specific association of rs6742078 was confirmed in samples from South America (P(men) = .046; odds ratio(recessive), 2.19; P(women) = .96). CONCLUSIONS: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required regarding the sex-specific physiology of bilirubin and bile acid metabolism. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Bilirrubina/sangue , Cálculos Biliares , Doença de Gilbert , Glucuronosiltransferase/genética , Transportadores de Ânions Orgânicos/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Adulto , Feminino , Cálculos Biliares/epidemiologia , Cálculos Biliares/genética , Cálculos Biliares/metabolismo , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla , Genótipo , Alemanha/epidemiologia , Doença de Gilbert/epidemiologia , Doença de Gilbert/genética , Doença de Gilbert/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , América do Sul/epidemiologiaRESUMO
We have previously observed that UCB binds to ZnSO4 in vitro, and suppressed the biliary bilirubin secretion in the hamster. The aim of this study was designed to investigate whether Zn salts might inhibit the enterohepatic cycling of UCB in subjects with Gilbert s syndrome. Fifteen patients with Gilbert s syndrome and 5 normal healthy volunteers were included in this study according to the following criteria: fasting hyperbilirubinemia, no hemolysis, and free of any medication. Patients were randomly assigned to receive acute o chronic treatment. Subjects treated in acute form and normal healthy volunteers were treated with 40 mg of ZnSO4 in a single dose, where as patients treated in chronic form received 100 mg ZnSO4 in a single dose daily for 7 days. The serum UCB levels (mg/dL) decreased from 2.64 +/- 1.04 to 2.02 +/- 0.87 (p < 0.001) and 1.8 +/- 0.36 to 1.48 +/- 0.32 (p < 0.005) in subjects treated in acute an chronic form respectively, but not in the control group. Whereas, the serum Zn levels (mg/dL) increased from 96.3 +/- 16.8 to 118.8 +/- 19. 5, (p < 0.01) and from 117.6 +/- 8.5 to 130.7 +/- 6.6 (p < 0.03) in subjects treated in acute an chronic form and also in subjects in the control group (98.0 +/- 7.3 to 128.0 +/- 21.9) p < 0.03. This study showed that acute and chronic oral administration of ZnSO4 decreased serum UCB levels significantly in subjects with Gilbert s syndrome. Most likely by the inhibition of the "normal" enterohepatic cycling of UCB.
Assuntos
Bilirrubina/metabolismo , Doença de Gilbert/tratamento farmacológico , Doença de Gilbert/metabolismo , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Sulfato de Zinco/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Zinco/antagonistas & inibidores , Zinco/sangueRESUMO
Fasted Bolivian squirrel monkeys (BoSM) exhibit a marked hyperbilirubinemia when compared to fed BoSM. This fasting hyperbilirubinemia (FH) is similar to that in human patients with Gilbert's syndrome. Endogenous bilirubin (BR) excretion (production) into bile was elevated two-fold in BoSM upon fasting. The fraction of injected dose of 3 H-amino-levulinic acid (ALA) incorporated into biliary BR in fasted monkeys was of less magnitude than in fed monkeys and was associated with lower specific activities of 3 H-BR. Both the lower incorporation of ALA and lower specific activities of 3H-BR in fasted BoSM suggest that increased BR excreted may have arisen from pre-existing non-labeled pools of either heme or BR.
Assuntos
Bile/metabolismo , Bilirrubina/metabolismo , Doença de Gilbert/veterinária , Doenças dos Macacos/metabolismo , Saimiri , Ácido Aminolevulínico , Animais , Bile/química , Bilirrubina/análise , Bilirrubina/sangue , Bolívia , Feminino , Doença de Gilbert/metabolismo , MasculinoRESUMO
Pulmonary carbon monoxide (CO) excretion rates (VeCO) were 50% greater, on average, in Bolivian squirrel monkeys (BoSMs) which exhibit a unique fasting hyperbilirubinemia (FH), than in fasted control Brazilian squirrel monkeys (BrSMs). Since the catabolism of heme produces equimolar amounts of CO and bilirubin, the increased VeCOs are consistent with concurrent increases in endogenous bilirubin production rates. Tin-protoporphyrin, a competitive inhibitor of heme oxygenase, significantly decreased both the VeCO and serum bilirubin level in fasted BoSMs. Overproduction of bilirubin may be responsible in part for the marked FH in BoSMs.
Assuntos
Monóxido de Carbono/metabolismo , Hiperbilirrubinemia/veterinária , Pulmão/metabolismo , Doenças dos Macacos/metabolismo , Saimiri/metabolismo , Animais , Bilirrubina/sangue , Bolívia , Brasil , Modelos Animais de Doenças , Jejum , Doença de Gilbert/metabolismo , Hiperbilirrubinemia/metabolismo , Masculino , Metaloporfirinas/farmacologia , Protoporfirinas/farmacologiaAssuntos
Hiperbilirrubinemia , Doença de Gilbert/diagnóstico , Doença de Gilbert/metabolismo , Doença de Gilbert/fisiopatologia , Hiperbilirrubinemia Hereditária/diagnóstico , Hiperbilirrubinemia/terapia , Icterícia Idiopática Crônica/diagnóstico , Icterícia Neonatal/fisiopatologia , Síndrome de Crigler-Najjar/diagnóstico , Síndrome de Crigler-Najjar/fisiopatologiaRESUMO
O fenótipo acetilador da isoniazida foi investigada em 19 pacientes caucasóides portadores de síndrome de Gilbert, por intermédio da avaliaçäo do percentual de acetil-isoniazida na urina. A proporçäo de acetiladores lentos entre os pacientes com síndrome de Gilbert foi semelhante àquela verificada em um grupo controle de caucasóides. Conclui-se que na síndrome de Gilbert näo há interferência na capacidade hepática de acetilaçäo da isoniazida
Assuntos
Humanos , Masculino , Feminino , Doença de Gilbert/metabolismo , Isoniazida/metabolismo , Acetilação , Acetiltransferases/metabolismo , Fígado/enzimologia , Isoniazida/genética , Isoniazida/urina , FenótipoRESUMO
Phenotyping of isoniazid acetylators in 19 Caucasoid patients with Gilbert's syndrome was achieved by evaluating the percentual of acetylisoniazid in the urine. The proportion of slow acetylators among the patients with Gilbert's syndrome was similar to those found among Caucasoids of control group. The conclusion was that Gilbert's syndrome doesn't interfere in the hepatic capacity of isoniazid acetylation.