Comments on disclosure of financial interest.
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Conflict of Interest↗
Biomedical subjects
C E Cornelius
Publications and source records attributed to C E Cornelius.
Research training for veterinarians and graduate education in veterinary medical colleges.
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Education, Graduate↗
Fasting hyperbilirubinemia in Bolivian squirrel monkeys with a Gilbert's-like syndrome.
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.
Animals↗
Bilirubin production and conjugation from newly formed heme in isolated rat hepatocytes.
1. Heme synthesis from delta-aminolevulinic acid (delta-ALA) in freshly isolated rat hepatocytes was maximal at 100 microM with a rate of approx. 7 nmol being synthesized per g wet weight cells. 2. Approximately 8% of synthesized heme was converted to bilirubin and 50% of the newly synthesized bilirubin was conjugated. 3. The ratio of di to monoconjugate was approx. 2.5. Incorporation of delta-ALA into bilirubin was increased by additional delta-ALA, heme and was also doubled in cells isolated from animals treated with CoCl2. 4. Bilirubin formation was inhibited approx. 90% by in vitro treatment with heme oxygenase inhibitors zinc and tin protoporphyrin.
Aminolevulinic Acid↗
Bile pigments in gallbladder and freshly-secreted hepatic duct bile from fed and fasted rainbow trout, Oncorhynchus mykiss.
1. Chromatographic analyses of bile pigments in rainbow trout reveal the presence of primarily unconjugated biliverdin (BV) and bilirubin (BR) glycosyl conjugates. Only trace amounts of unconjugated BR are present in hepatic duct (HD) bile: no beta-glucuronidase activity is detectable. 2. The per cent of BV and BR in HD and gallbladder biles is similar in fasted trout; however, the per cent of BV is significantly increased in HD bile from fed fish. 3. Fasting decreases the rate of choleresis but does not alter the excretory rate of endogenous BV or BR. 4. Erythrocyte life span is estimated to be approximately 500 days.
Animals↗
Fasting hyperbilirubinemia in normal squirrel monkeys.
The plasma of Bolivian squirrel monkeys, unlike that of Brazilian squirrel monkeys, is markedly yellow due to unconjugated hyperbilirubinemia after an overnight fast. The fasting hyperbilirubinemia in Bolivian squirrel monkeys is likely due to two mechanisms. First, a twofold increase in the bilirubin turnover/production rate occurs during a 24-hour fast. A second mechanism is the decreased hepatic conjugation potential for bilirubin due to the presence of a higher bilirubin UDP-glucuronosyltransferase 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 Bolivian squirrel monkey provides an excellent animal model for human Gilbert's syndrome type I in which to study rate-limiting mechanisms in the movement of bilirubin from plasma to bile.
Animals↗
Kinetic properties of bilirubin UDP-glucuronyltransferase in squirrel monkeys exhibiting fasting hyperbilirubinemia.
1. Bolivian squirrel monkeys (BoSM), unlike Brazilian squirrel monkeys (BrSM), exhibit a marked fasting hyperbilirubinemia (FH) and serve as animal models for Gilbert's syndrome type I. 2. Compared to BrSM, BoSM possess a higher apparent UDPGAKm (0.51 vs 0.29 mM) and lower Vm (0.36 vs 0.48 nmol BR conjugated/min per mg microsomal protein) for hepatic bilirubin (BR) UDP-glucuronyl-transferase (BR UDPG-T). 3. Lineweaver-Burk plots are linear and obey Michaelis-Menten kinetics when UDP-acetylglucosamine is used as activator and UDPGA substrate concentrations are within the physiologic range present in the liver during the fed and fasted state (0.10-0.71 mM); above these concentrations, there is a discontinuity of kinetic plots as noted in other species. 4. There is no effect of fasting on the Km of BR conjugation (i.e. sum of mono- and diglucuronides) in either monkey; however, fasting is associated with lower Vm values (15-20%) in each subspecies. 5. By calculating the potential BR flux (nmol BR conjugated/min per kg) using known hepatic UDPGA concentrations, liver weights and in vitro Km and Vm, a markedly lower BR flux is observed in BoSM (58.4 nmol/min per kg) than in BrSM (91.6 nmol/min per kg). 6. Significantly higher apparent UDPGAKm and lower Vm of BR UDPG-T for conjugation of BR to BR monoglucuronide appears responsible in part for the four- to five-fold elevations in unconjugated BR in the liver and plasma in the fasted BoSM.
Animals↗
Endogenous bilirubin excretion in Bolivian squirrel monkeys with a Gilbert's-like syndrome.
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.
Aminolevulinic Acid↗
Hepatic bilirubin and UDP-glucuronate levels in Bolivian squirrel monkeys exhibiting fasting hyperbilirubinemia.
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.
Animals↗
Increased carbon monoxide excretion in Bolivian squirrel monkeys with fasting hyperbilirubinemia.
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.
Animals↗
Bilirubin excretion and bile flow in fed and fasted Brazilian squirrel monkeys (Saimiri sciureus).
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.
Animals↗
Biliverdin reductase activity in cattle, sheep, rabbits and rats.
1. Biliverdin reductase (BVR) activity was measured in post-microsomal supernatants of livers of cattle, sheep, rabbits and rats. BVR activities in bovine and ovine livers were 4.7 and 5.0%, respectively, of rat liver activity. 2. The finding of BVR activity in ruminants is in contrast to a previous report and may be due to the use of a different assay system. 3. Lapine liver had the lowest BVR activity of only 0.37% of rat liver activity. 4. Increasing the available heme by phenylhydrazine administration did not induce increased hepatic or splenic BVR activity in rabbits. 5. Maximal BVR activities were attained using NADPH as cofactor at pH 8.7 in sheep and rabbits and at pH 8.4 in cattle. 6. Differing concentrations of bovine or human albumins enhanced or inhibited BVR activity quite differently in the various species. 7. The finding of a very low, but measurable BVR activity in lapine liver and spleen may explain, in part, why rabbits, unlike rats, cattle and sheep, excrete primarily biliverdin (70%) into bile.
Anemia, Hemolytic↗
Elevation in plasma glucagon levels in response to stress in squirrel monkeys: comparisons of two subspecies (Saimiri sciureus boliviensis and Saimiri sciureus sciureus).
Bolivian (Bo) and Brazilian (Br) squirrel monkeys (SMs) were captured and restrained to determine patterns of glucagon and glucose response. In both subspecies, plasma glucagon and glucose levels rose rapidly in response to restraint procedures; glucagon levels in BrSMs and glucose levels in both subspecies returned to basal values in 15 minutes. The magnitude of the glucagon and glucose responses differed significantly between BoSMs and BrSMs.
Animals↗
A review of new approaches to assessing hepatic function in animals.
Although a multitude of effective liver function tests are available for use in animals, a variety of modifications of currently used tests have been recently reported. In addition, newer procedures now used in human medicine may also provide unique insights into assessing and detecting acquired hepatic disorders in animals. Examples of new procedures are: assessing microsomal mixed function oxidase activity by plasma caffeine clearance; estimating the extent of active hepatic fibrogenesis through serum procollagen-III peptide levels; determining hepatic blood flow and functional mass by the galactose elimination capacity; detecting primary hepatocellular cancer through serum or urinary ligandin levels; and to estimate the liver's maximal capacity to excrete indocyanine green independent of blood flow. In evaluating drugs as to their hepatotoxicity, function tests should be included in the liver profile which measure specific metabolic alterations unique to the compound under study.
Animals↗
Characterization of Gilbert-like syndrome in squirrel monkeys (Saimiri sciureus).
Bolivian squirrel monkeys, unlike those of Brazilian origin, exhibit a marked fasting hyperbilirubinemia (FH) similar to that observed in Gilbert's syndrome in man. Since no delays in the hepatic clearance of sulfobromophthalein or indocyanine green are present, the Bolivian monkey appears to be similar to Gilbert's type I syndrome. FH can be significantly decreased by either phenobarbital or tin-protoporphyrin pretreatment. Nicotinic acid-induced hyperbilirubinemia and delayed tolbutamide clearance were not observed as in the human syndrome.
Animals↗
Prevention of neonatal hyperbilirubinemia in rhesus monkeys by tin-protoporphyrin.
Rhesus monkey infants were injected subcutaneously at birth with 12 to 100 mumol of tin-protoporphyrin IX, a competitive inhibitor of microsomal heme oxygenase. The elevated unconjugated serum bilirubin levels of the neonates receiving this metalloporphyrin rapidly declined to near adult levels by 24-30 h. Control neonates which received an injection of saline exhibited normal physiologic hyperbilirubinemias of from 3-6 mg/dl by 12-24 h as expected. These studies establish the effectiveness of tin-protoporphyrin IX in depressing bilirubin production and preventing physiologic hyperbilirubinemia in simian neonates. Two of six animals receiving the metalloporphyrin exhibited signs of toxicity.
Animals↗
Nonhuman primates with spontaneous diseases as animal models.
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Animals↗