Bilirubin excretion in rats with normal and impaired bilirubin conjugation: effect of phenobarbital

Robinson, Stephen H.; Yannoni, Claudine; Nagasawa, S

doi:10.1172/jci106761

Cited by 55 publications

(17 citation statements)

References 34 publications

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“…Although the heterozygous animals did not usually manifest hyperbilirubinemia of such magnitude as the homozygous rats, the wide range of standard deviations in the former group bear out heterogeneity of genetic expression in these ani mals. The liver weight to body weight ratios in the Gunn rats were significantly lower than the Wistar controls as has been reported previously (23). Levels of protein (table II) in whole microsomes and smooth microsomes did not differ significantly in the three groups of animals.…”

Section: Plasma Bilirubin Liver Weight and Drug Metabolismsupporting

confidence: 78%

Submicrosomal Distribution of Hepatic Drug-Metabolizing Components in the Gunn Rat

Guarino¹,

Reagan²,

Gram³

1973

Pharmacology

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The submicrosomal distribution of a number of enzymes involved in the metabolism of xenobiotics was studied in livers of Wistar and Gunn rats. Compared with Wistar controls, ethyl morphine demethylase activity and cytochrome P-450 levels in smooth microsomes of homozygous Gunn rats were significantly decreased (about 20 %). On the other hand, both heterozygous and homozygous Gunn rats exhibited significantly elevated (20–60 %) NADPH cytochrome c reductase activities in both smooth and rough microsomal fractions. UDP-glucuronyltransferase activity measured with phenolphthalein as substrate was barely detectable (<10 % of Wistar control) in smooth or rough microsomes of homozygous Gunn rats, but was only slightly reduced in the heterozygous animals.

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Section: Plasma Bilirubin Liver Weight and Drug Metabolismsupporting

confidence: 78%

Submicrosomal Distribution of Hepatic Drug-Metabolizing Components in the Gunn Rat

Guarino¹,

Reagan²,

Gram³

1973

Pharmacology

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“…In addition, we investigated the direct conversion of BMG to BDG by rat liver microsomes and evaluated the effect of pretreating the animals with phenobarbital to enhance hepatic conjugating ability (21). We found that rat liver microsomes contain a UDP-glucuronic acid-dependent enzyme system that converts bilirubin or BMG to BDG and that the activity of this enzyme system is enhanced by pretreatment of the animals with phenobarbital.…”

mentioning

confidence: 99%

Bilirubin diglucuronide synthesis by a UDP-glucuronic acid-dependent enzyme system in rat liver microsomes.

Blanckaert¹,

Gollan²,

Schmid³

1979

Proc. Natl. Acad. Sci. U.S.A.

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Incubation of rat liver homogenate or microsomal preparations with bilirubin or bilirubin monoglucuronide with (BMG) In humans and other mammals, bilirubin is excreted in bile largely in the form of glycosidic conjugates. These are formed in the liver by esterification of one or both propionic acid side chains of the pigment with glucuronic acid (1, 2) or, to a lesser extent, with glucose or xylose (3-5). Bilirubin diglucuronide (BDG) has been identified as the major conjugate in the bile of adult humans, rats, dogs, and cats (1, 2, 5). Formation of BDG probably proceeds in two enzyme-catalyzed steps-i.e., synthesis of bilirubin monoglucuronide (BMG) and conversion of it to BDG (6). Whereas the enzyme involved in hepatic formation of BMG has been identified as a microsomal glucuronosyltransferase [UDP glucuronate (3-glucuronosyltransferase (acceptor-unspecific), EC 2.4.1.17] with UDP-glucuronic acid serving as the carbohydrate donor (7), the mechanism and subcellular location of the conversion of BMG to BDG remain controversial. In animals that excrete predominantly BDG, liver tissue preparations incubated at pH 7.4-7.8 under standard conditions with 164-300 1iM bilirubin and 2.8-5.0 mM UDPglucuronic acid synthesize almost exclusively BMG (6,8,9).This observation led to a search for a nonmicrosomal enzyme system that converts BMG to BDG. It recently has been reported (10) that this reaction involves transesterification that is catalyzed by bilirubin glucuronide glucuronosyltransferase and does not require UDP-glucuronic acid. This enzyme, identified in rat liver plasma membrane preparations, converts 2 mol of BMG to 1 mol of BDG and 1 mol of bilirubin (10). This catalytic activity has been detected also in liver preparations of homozygous Gunn rats (11) which exhibit congenital unconjugated hyperbilirubinemia due to deficiency of hepatic bilirubin UDP-glucuronosyltransferase activity (BGTase) (12, 13).Because in intact Sprague-Dawley rats or homozygous Gunn rats we have been unable to obtain evidence for formation of BDG by transglucuronidation of BMG (14), we reevaluated the mechanism by which bilirubin is conjugated by the microsomal system. The observation that, in conditions associated with decreased hepatic BGTase (e.g., Gilbert syndrome, CriglerNajjar disease) and in heterozygous Gunn rats, bile contains predominantly BMG (15-18) suggested that, in the presence of high hepatic bilirubin concentrations relative to the conjugating enzyme activity, the liver may preferentially form BMG. This was supported by the additional finding that BMG excretion is proportionally enhanced in normal rats infused intravenously with bilirubin (19). The standard procedure for assaying microsomal BGTase (6) utilizes bilirubin concentrations (164-300 ,uM) greatly in excess of those present in normal rat liver; under steady-state conditions of hepatic bilirubin transport in the rat, the bilirubin concentration in the liver is of the same order of magnitude as the plasma concentration (20), approximately 0.5 ,4M (unpubl...

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“…Treatment with TCDD caused a 16-fold increase in benzo[a]pyrene hydroxylase activity, from 0.5 ± 0.1 to 8.2 i 0.9 ,umol of phenols formed per g of liver per hr (P < 0.001). By contrast, no bilirubin-UDPglucuronate transferase activity was detected in either control or TCDDtreated animals (1,9). DISCUSSION This paper reports successful chemical stimulation of the alternate pathways of bilirubin catabolism in the jaundiced Gunn rat.…”

mentioning

confidence: 67%

“…To explain this lack of response to phenobarbital, it has been assumed that the Gunn rats and the patients lack the genetic information necessary for synthesis of bilirubin-UDPglucuronate transferase (6)(7)(8)(9) and that the alternate pathways of bilirubin metabolism are not mediated by the mixed-function monooxygenases that respond to treatment with phenobarbital (9,10). Because phenobarbital induces preferentially the cytochrome P4W system (11,12), we have treated jaundiced Gunn rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent known inducer of microsomal cytochrome P448 (P1450) (13), to determine its effect on metabolism of unconjugated bilirubin.…”

mentioning

confidence: 99%

Stimulation of bilirubin catabolism in jaundiced Gunn rats by an inducer of microsomal mixed-function monooxygenases

Kapitulnik

Ostrow

1978

Proc. Natl. Acad. Sci. U.S.A.

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Bilirubin excretion in rats with normal and impaired bilirubin conjugation: effect of phenobarbital

Cited by 55 publications

References 34 publications

Submicrosomal Distribution of Hepatic Drug-Metabolizing Components in the Gunn Rat

Submicrosomal Distribution of Hepatic Drug-Metabolizing Components in the Gunn Rat

Bilirubin diglucuronide synthesis by a UDP-glucuronic acid-dependent enzyme system in rat liver microsomes.

Stimulation of bilirubin catabolism in jaundiced Gunn rats by an inducer of microsomal mixed-function monooxygenases

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