RESUMO
Fasting unconjugated hyperbilirubinemia in Bolivian squirrel monkeys is most likely due to two mechanisms. First, a twofold increase in bilirubin production/turnover occurs during fasting. Increased bilirubin production is subsequently accompanied by increased amounts of unconjugated bilirubin in the hepatic cytosol, which requires conjugation for excretion. The presence of a twofold greater concentration of bilirubin in the livers of fed BoSM with the Gilbert's-like syndrome than in fed control Brazilian squirrel monkeys (BrSM) clearly establishes the presence of an innate subspecies difference, even without the effects of fasting. A second mechanism, which is responsible in part for FH in BoSM, is the presence of a hepatic enzyme, UDP-glucuronyl transferase, which has a higher apparent UDPGAKm and a lower Vm; this results in higher steady-state plasma and hepatic bilirubin levels during a fast when hepatic UDP-glucuronic acid levels are low. The BoSM provides the investigator with an excellent animal model for human Gilbert's syndrome type I in which to study rate-limiting mechanisms in the transport of bilirubin from plasma to bile.
Assuntos
Bilirrubina/metabolismo , Modelos Animais de Doenças , Jejum , Doença de Gilbert/etiologia , Saimiri/metabolismo , Animais , Glucuronosiltransferase/metabolismo , HumanosRESUMO
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/farmacologiaRESUMO
1. Bolivian squirrel monkeys (BoSMs), which are animal models for Gilbert's syndrome, have 40% less hepatic bilirubin UDP-glucuronyltransferase (BR-UPPG-T) activity than Brazilian squirrel monkeys (BrSMs). 2. Although fasting results in similar decreases in hepatic UDP-glucose and UDP-glucuronate levels in both simian subspecies, increased activities (55%) of BR-UDPG-T are induced only in the fasted control BrSMs, which do not exhibit the marked fasting hyperbilirubinemia (FH). 3. Total hepatic bilirubin (BR) concentrations were 50% greater in both fed and fasted BoSMs when compared to BrSMs. 4. Hepatic unconjugated BR levels increase upon fasting only in Gilbert-like BoSMs, reaching concentrations twice that observed in BrSMs. 5. Elevated hepatic BR levels in fasted BoSMs may reflect BR overproduction or inadequate glucuronidation. 6. The increased BR-UDPG-T activity induced in BrSMs during fasting could compensate in-part for the UDPGA depletion and prevent the marked FH as observed in BoSMs.
Assuntos
Bilirrubina/metabolismo , Jejum , Glucuronosiltransferase/metabolismo , Hiperbilirrubinemia/metabolismo , Fígado/enzimologia , Uridina Difosfato Ácido Glucurônico/metabolismo , Açúcares de Uridina Difosfato/metabolismo , Animais , Bilirrubina/sangue , Feminino , Glicogênio/metabolismo , Fígado/metabolismo , Saimiri , Uridina Difosfato Glucose/metabolismo , Uridina Difosfato Ácido Glucurônico/sangueRESUMO
Fasted Brazilian squirrel monkeys (BrSMs) exhibited slightly higher serum bilirubin levels (0.30 +/- 0.05 mg/dl) than others in the fed state (0.13 +/- 0.01). The mean liver weight was 50% lower following a 22 h fast. The rate of bile flow was unaffected by fasting and averaged 13.8 microliters/min/kg and 47.5 microliters/min/100g liver in six BrSMs. No significant difference in mean bilirubin excretion/min was observed on a body weight basis following fasting. When the mean rate of bilirubin excretion was calculated as a function of liver weight, a two-fold higher rate was present in fasted monkeys, but only at the p = 0.06 level of statistical significance. From data collected in this and earlier studies, it would appear that BrSMs represent the best animals studied to date to serve as experimental controls in comparative studies with Bolivian squirrel monkeys which exhibit a Gilbert-like syndrome.