Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemically induced diabetes has been reported to induce profound changes in bile formation, but possible toxic effects of the streptozotocin or alloxan used cannot be excluded totally. This study was undertaken to evaluate biliary function in spontaneously diabetic female biobreeding rats with a diabetes duration of 2 wk and compare them with nondiabetic littermates. Diabetic animals evidenced glycosuria, hyperglycemia and hypoinsulinemia. Biliary concentration and secretion of bile acids, cholesterol and phospholipids were significantly increased, with no enhancement in the lithogenic index of bile. Bile flow and the biliary secretion of sodium, potassium, chloride and bicarbonate were significantly reduced despite the increased bile acid secretion. The cholestatic condition was confirmed by an increased serum concentration of bile acids and a higher activity in serum of the alkaline phosphatase liver isoenzyme. Biliary calcium concentration increased without any change in its serum concentration. A linear relationship was observed between biliary calcium and bile acid secretion. Serum concentration of unconjugated and of conjugated bilirubin was increased 1.6-fold and 8-fold, respectively, with a 1.5-fold enhanced biliary secretion of bilirubins despite the cholestasis; this points to an enhanced bilirubin production. An increased proportion of conjugated bilirubin was found in serum together with an enhanced bilirubin diconjugate/monoconjugate ratio in bile. A higher UDP-glucuronyltransferase activity and a delayed transit of bilirubin could account for these effects. Administration of insulin to diabetic animals tended to reverse the above reported changes. The spontaneously diabetic biobreeding rat thus represents a model of bile acid-independent cholestasis with enhanced biliary bile acid and calcium secretion and with presumably an enhanced bilirubin production.
 ...
PMID:Spontaneously diabetic biobreeding rats and impairment of bile acid-independent bile flow and increased biliary bilirubin, calcium and lipid secretion. 163 53

Serum concentrations of nonglucuronidated-nonsulfated, glucuronidated, and sulfated bile acids in 9 control children and 16 children with cholestasis were quantitated by mass fragmentography. Total bile acid levels in control children were 19.55 +/- 2.78 mumol/liter (mean +/- SEM), and glucuronidated and sulfated bile acids comprised 2.6 +/- 0.5 and 17 +/- 3.1%, respectively. In 9 patients with congenital biliary atrasia, total bile acid levels were 167.34 +/- 11.18 mumole/liter of which 2.1 +/- 0.3% were glucuronidated and 15 +/- 1.4% were sulfated. Lithocholic and 3 beta-hydroxy-5-cholenoic acids, which have hepatotoxic effects, were presented in only small amounts in cholestatic children, and they were almost all glucuronidated or sulfated. The percentages of glucuronidated bile acids in control and cholestatic children were lower than in healthy and cholestatic adults, which may be explained by the lower activity of UDP-glucuronyltransferase in neonatal liver.
 ...
PMID:Serum concentrations of glucuronidated and sulfated bile acids in children with cholestasis. 401 35

The glucuronidation of bile acids is an important pathway for the detoxification and elimination of retained bile acids during cholestasis. A 3-OH-specific androgen UDP-glucuronyltransferase was purified from solubilized female rat liver microsomes using Chromatofocusing and UDP- hexanolamine -Sepharose 4B affinity chromatography. The purified 3-OH androgen UDP-glucuronyltransferase is reactive towards bile acids, including lithocholic acid, deoxycholic acid, and ursodeoxycholic acid, in addition to the androgenic steroids etiocholanolone and androsterone. The highest activity towards bile acids is seen with lithocholic acid-24-methyl ester, and no activity is seen with lithocholic acid-3 alpha-sulfate or 5 beta- cholanic acid-3-one. No glucuronidation activity towards bile acids was observed with either a purified 17-OH steroid UDP-glucuronyltransferase or a p-nitrophenol-UDP-glucuronyltransferase. Lithocholic acid competitively inhibits etiocholanolone glucuronidation by the purified 3-OH androgen isoenzyme. These results suggest that a UDP-glucuronyltransferase isoenzyme is present in female rat liver which is capable of specifically glucuronidating the 3-OH group of bile acids and androgenic steroids.
 ...
PMID:Glucuronidation of bile acids by rat liver 3-OH androgen UDP-glucuronyltransferase. 642 9

The effect of phenobarbital treatment on bilirubin metabolism and bile secretion was studied in a patient with Crigler-Najjar syndrome, type II and acquired cholestasis. Following cholecystectomy and choledochostomy, a balloon inflatable T tube was inserted to facilitate bile collection. Hepatic UDP-glucuronyltransferase in surgically obtained liver tissue was 25% of normal activity and bilirubin monoconjugates accounted for greater than 80% of the pigments in bile. Phenobarbital therapy decreased the concentration of fasting serum bile acids by 33% and partially reestablished their enterohepatic cycling postprandially. The total fasting serum bilirubin concentration (greater than 90% unconjugated) increased 21% during phenobarbital treatment and was unaffected by caloric intake. Bile flow was increased 2.7 times after phenobarbital treatment. The biliary concentration of total bilirubin was increased 2.4 times, primarily due to monoconjugated bilirubin, which accounted for 91% of the biliary pigments. Bile acid, phospholipid, cholesterol, and calcium concentrations in bile were significantly increased after phenobarbital. The data indicate that even in the presence of cholestasis an underlying deficiency in bilirubin conjugation may be confirmed by biliary pigment analysis.
 ...
PMID:Effect of phenobarbital on serum and biliary parameters in a patient with Crigler-Najjar syndrome, type II and acquired cholestasis. 687 8

Phospholipid fatty acid composition and bilirubin UDP-glucuronyltransferase activity from liver microsomal membrane were studied in normal and in bile duct ligated rats. Incubation of normal microsomes with 15 microM bilirubin (considered as physiological concentration) yielded 60% bilirubin diglucuronide; in 2 days post-cholestatic rats, they showed 20% bilirubin diglucuronide which was undetectable in 8 days post-cholestatic group. When compared to controls, after 2 days of cholestasis, microsomal phospholipids showed a clear decrease in linoleic and arachidonic acids and an increment in palmitic and stearic acids. 8 days post-cholestatic rats presented a marked increase in palmitic, oleic and docosaexaenoic acids, while linoleic and arachidonic acids decreased. Cholestasis produced disturbances in microsomal phospholipids fatty acid composition; but these changes are unable to explain entirely the severe damage observed in bilirubin diglucuronide formation.
 ...
PMID:Liver microsomal phospholipid fatty acids behavior and its relationship to bilirubin UDP-glucuronyltransferase activity in bile duct ligated rats. 854 80

The effects of chronic administration of aflatoxin B1 (AFB1) on liver drug metabolism enzymes were measured in New Zealand rabbits divided into three groups of 5 animals, each receiving over 5 days either arabic gum or AFB1 in arabic gum at a daily oral dose of 0.05 or 0.10 mg/kg. These treatments did not lead to any lethality in any of the treated groups, but the body weight gain was altered. Biochemical exploration of plasma components revealed a dose-dependent hepatotoxicity characterized by cytolysis and cholestasis. At 0.10 mg/kd/day of AFB1, significant decreases were observed in total liver microsomal cytochrome P450, several P450-dependent monooxygenase activities, all individual P450 isoenzymes levels analysed by Western-blotting and glutathione S-transferase activities. By contrast, at 0.05 mg/kg/day of AFB1, even though total cytochrome P450 was decreased by 30%, only P450 1A1 and 3A6 isoenzymes, and aniline hydroxylation, pentoxyresorufin O-depentylation, aminopyrine, erythromycin, ethylmorphine and dimethylnitrosamine N-demethylations were affected. In the same animal group, the only glutathione S-transferase accepting CDNB (1-chloro-2,4-dinitrobenzene) as substrate was decreased by 22%. UDP-glucuronyltransferase accepting p-nitrophenol as substrate was increased in both groups of animals (33-62%). The mechanisms that could contribute to the observed changes in drug metabolizing enzymes are discussed.
 ...
PMID:Dose-related effect of aflatoxin B1 on liver drug metabolizing enzymes in rabbit. 864 16

Aflatoxin B1 (AFB1) has been reported to decrease microsomal hepatic cytochrome P450 (P450) content and increase both total plasma bilirubin concentration and liver heme oxygenase activity. The purposes of this study were to determine whether liver hemoproteins contents and heme catabolizing enzymes were affected by the mycotoxin and whether these alterations were linked to hyperbilirubinemia. Male New Zealand rabbits were divided into three groups of five animals, each receiving for 5 days either arabic gum as vehicle or AFB1 at a daily oral dose of 0.05 or 0.10 mg/kg. These treatments affected neither cytochrome b5 content nor NADPH-cytochrome reductase activity. A linear dose-dependent decrease in cytochrome P450 content and increases in both heme oxygenase and biliverdin reductase activities were observed. Bilirubin UDP-glucuronyltransferase activity was dramatically decreased at both doses, whereas cholestasis occurred only at 0.10 mg/kg. An exponential dose-dependent increase in plasma bilirubin concentration was also observed. Both the simultaneous exponential increase in bilirubinemia associated to a reduced bilirubin UDP-glucuronyltransferase activity and the absence of cholestasis at 0.05 mg/kg, suggested that the hyperbilirubinemia is more probably related to an increased heme catabolism than to an altered bile duct permeability.
 ...
PMID:Dose-related increase in liver heme catabolism during rabbit aflatoxicosis. 929 32