Charles E. Cornelius

Maximal biliary excretion of sulfobromophthalein sodium in sheep.

Sulfobromophthalein sodium (BSP) and taurocholic acid were infused into unanesthetized female sheep which were previously prepared with biliary cannulae for quantitative bile collection. Submaximal BSP excretion (below the maximal excretory capacity of the liver) was proportional to the BSP-infusion rate and independent of changes in the bile-flow rate subsequent to varied rates of taurocholic-acid infusion. During maximal BSP excretion, the biliary BSP concentration was constant (approximately 15 mg/ml), and the maximal excretion rate varied directly with the bile-flow rate. Secretin infusion during maximal or submaximal BSP-infusion trials increased bile flow by 30% but did not affect the BSP-excretion rate.

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.

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.

A review of new approaches to assessing hepatic function in animals

Although a multitude of effective liver function tests are avaiable 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 livers 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.

Hepatic bilirubin and UDP-glucuronate levels in bolivian squirrel monkeys exhibiting fasting hyperbilirubinemia

1. Bolivian squirrel monkeys (BoSMs), which are animal models for Gilberts 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.

Effect of Fasting on Bilirubin Metabolism

PLASMA unconjugated bilirubin (UCB) levels increase within the first two days of restricted dietary intake or fasting. As concluded by Felsher, Rickard and Redeker in this issue of the Journal, ele...

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 Gilberts 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.

Nonhuman primates with spontaneous diseases as animal models

Studies during the last decade have substantially increased our basic knowledge concerning the nature of spontaneous diseases occurring in captive and wild nonhuman primates. Continuing research on captive populations at the seven National Institutes of Health-supported primate research centers and a variety of other laboratories has now uncovered many unique animal models for future comparative investigations with man. Such epidemiologic and biomedical studies also allow animal scientists to better understand the medical problems of simian primates and to provide rational approaches for their maintenance and treatment. Such investigations will ultimately be necessary for the preservation of certain endangered species. Detailed studies on such animal model systems will no doubt provide new clues to mechanisms in the pathogenesis of human counterpart syndromes. Examples of such spontaneous diseases that occur in a variety of organ systems in nonhuman primates are presented in Table I. Although only diseases that occur spontaneously are presented in this brief editorial, the nonhuman primate has and is currently being used in a multitude of highly significant experimental studies such as those concerned with hepatitis A, 6, and non-A, non-B infections; atherosclerosis; kuru; leprosy; herpes oncogenesis; effects of photochemical pollutants on the lung; fetal corrective surgery; and teratogenic effects of a variety of drugs, to mention only a few 1121. It is well known that nonhuman primates offer certain

Chemical and hematological studies on blood of bovine dwarfs.

Summary 1. Serum proteins, calcium, magnesium, and phosphorus of “short-headed” bovine dwarfs are all within normal limits. 2. Serum cholesterol and protein-bound iodine levels are within the normal range and indicate that the “short-headed” bovine dwarf is not a primary thyroid cretin. 3. All hematological values appear normal except for the differential count. Deviations from the normal are discussed.

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 μl/min/kg and 47.5 μl/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 Bovilian squirrel monkeys which exhibit a Gilbert-like syndrome.