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Biomedical subjects

I M Arias

Publications and source records attributed to I M Arias.

At least 127 records · Page 7Linked to original sources
PubMed1978

Hepatic conversion of bilirubin monoglucuronide to diglucuronide in uridine diphosphate-glucuronyl transferase-deficient man and rat by bilirubin glucuronoside glucuronosyltransferase.

The microsomal enzyme uridine diphosphate (UDP) glucuronate glucuronyltransferase (E.C. 2.4.1.17) catalyzes formation of bilirubin mono-glucuronide from bilirubin and UDPglucuronic acid. Bilirubin glucuronoside glucuronosyltransferase (E.C. 2.4.1.95), an enzyme concentrated in plasma membrane-enriched fractions of rat liver, converts bilirubin monoglucuronide to bilirubin diglucuronide. Bilirubin glucuronoside glucuronosyltransferase activity was studied in homogenates of liver biopsy specimens obtained from patients with the Crigler-Najjar syndrome (Type I) and in subcellular liver fractions of rats homozygous for UDP glucuronate glucuronyltransferase deficiency (Gunn strain). In patients with the Crigler-Najjar syndrome (Type I) and in Gunn rats, hepatic UDPglucuronate glucuronyltransferase activity was not measurable; however, bilirubin glucuronoside glucuronosyltransferase activity was similar to that in normal controls. The subcellular distribution of bilirubin glucuronoside glucuronosyltransferase activity in Gunn rat liver was similar to the distribution observed in normal Wistar rat liver.When bilirubin monoglucuronide was infused intravenously into Gunn rats, 29+/-5% of the conjugated bilirubin excreted in bile was bilirubin diglucuronide. After transplantation of normal Wistar rat kidney, which contained UDPglucuronate glucuronyltransferase activity, in Gunn rats, the serum bilirubin concentration decreased by 80% in 4 days. The major route of bilirubin removal was biliary excretion of conjugated bilirubin, approximately 70% of which was bilirubin diglucuronide. Although patients with the Crigler-Najjar syndrome (Type I) and Gunn rats lack UDP glucuronate glucuronyltransferase, their livers enzymatically convert bilirubin monoglucuronide to diglucuronide in vitro. Conversion in bilirubin monoglucuronide to diglucuronide was demonstrated in Gunn rats in vivo.

Adult↗
PubMed1977

Enzymatic conversion of bilirubin monoglucuronide to diglucuronide by rat liver plasma membranes.

Formation of bilirubin monoglucuronide from unconjugated bilirubin requires a microsomal enzyme, UDP-glucuronate glucuronyltransferase (EC 2.4.1.17). Conversion of bilirubin monoglucuronide to bilirubin diglucuronide, the major bilirubin conjugate in bile, was studied in subcellular fractions of rat liver. The highest specific activity for bilirubin diglucuronide formation occurred in a fraction highly enriched in plasma membranes. Studies of reaction stoichiometry and utilization of UDP-D-[14C]glucuronic acid revealed that conversion of bilirubin monoglucuronide to bilirubin diglucuronide is not catalyzed by UDP-glucuronyltransferase, and results from transglucuronidation of bilirubin monoglucuronide, with formation of bilirubin diglucuronide and unconjugated bilirubin. When unconjugated bilirubin was infused intravenously into rats at rates exceeding the maximal hepatic excretory capacity, bilirubin monoglucuronide accumulated in serum and bilirubin diglucuronide was found exclusively in bile as the predominant bilirubin metabolite. These results suggest that formation of bilirubin diglucuronide occurs at the surface membrane of the liver cell. Conversion of bilirubin monoglucuronide to bilirubin diglucuronide may play a role in the transport of bilirubin glucuronides from liver to bile.

Animals↗
PubMed1977

Bilirubin metabolism in the spiny dogfish, Squalus acanthias, and the small skate, Raja erinacea.

1. The main bilirubin conjugate in bile of spiny dogfish (Squalus Acanthias) and small skate (Raja Erinacea) is bilirubin monoglucuronide. 2. Microsomal preparations from dogfish and small skate liver have similar bilirubin UDPglucuronyltransferase (UDPGT) activity and catalyze the conjugation of bilirubin with glucose from UDPglucose. 3. The activity of bilirubin glucosidation (UDPGT) was 0.5 times UDPG1T activity in dogfish and 0.15 times in skate liver microsomes. 4. Sodium cholate increased UDPGT and UDPG1T activities in dogfish and skate liver microsomal preparations only minimally, but the detergent markedly increased thermolability of UDPGT in skate liver microsomes.

Animals↗
PubMed1977

Ligandinuria in nephrotoxic acute tubular necrosis.

Ligandin (GSH-S-transferase B), an abundant intracellular soluble protein in rat proximal tubules, hepatocytes, and small intestinal mucosal cells, is believed to be a component of an organic anion transport system. Its presence in urine was determined immunologically and catalytically in adult, female, Sprague-Dawley rats that were given mercuric chloride or potassium dichromate. These nephrotoxic agents produce severe renal failure, with epithelial necrosis in the proximal tubule. Mercuric chloride perferentially injures the terminal part of the proximal tubule, while potassium dichromate damages more proximal segments. Ligandinuria was consistently detected immunologically and catalytically from 6 to 24 hr following injection of mercuric chloride. Potassium dichromate administration did not result in immunologically detectable liganduria; however, GSH-S-transferase activity, which provides a more sensitive assay, was frequently detected. The findings are consistent with immunofluorescent localization of ligandin in the proximal tubule. Immunologic or enzymatic measurement of ligandin in urine may provide a sensitive index of acute injury to the proximal tubule.

Acute Kidney Injury↗
PubMed1976

Bilirubin and biliverdin binding to rat Y protein (ligandin).

The binding of bilirubin to poly(L-lysine) produces an optically active complex at pH 10.1. Circular dichroism spectra of these complexes are distinguishable from those generated by binding of bilirubin to the high affinity sites on albumin. Comparison of the circular dichroism spectra of bilirubin bound to the hepatic protein ligandin with those of bilirubin complexed with albumin or polylysine indicates that binding of bilirubin to ligandin occurs at two types of sites. These are distinguishable on the basis of their spectral properties, one resembling the high affinity site of bovine serum albumin and the other resembling polylysine. Complexes of biliverdin with albumin and ligandin bear similarities to the bilirubin-protein complexes. The native protein itself has an ordered structure which consists of 41% alpha-helix and is not altered by the binding of bilirubin.

Animals↗
PubMed1976

Rotor's syndrome. A distinct inheritable pathophysiologic entity.

Urinary total, isomer I and isomer III coproporphyrin excretion was determined in 11 patients with Rotor's syndrome, 23 phenotypically normal family members, 16 patients with the Dubin-Johnson syndrome and 20 normal control subjects. Control subjects excreted 24.8 +/- 1.3 per cent (mean SEM) of urinary coproporphyrin as isomer I. Patients with the Dubin-Johnson syndrome excreted 88.9 +/- 1.3 per cent as urinary coproporphyrin I, and patients with Rotor's syndrome excreted 64.8 +/- 2.5 per cent as urinary coproporphyrin I, significantly different from the control subjects and the patients with the Dubin-Johnson syndrome (p less than 0.001). Eight phenotypically normal parents and children of patients with Rotor's syndrome excreted 42.9 +/- 5.4 per cent as urinary coproporphyrin I, intermediate between results in patients with Rotor's syndrome and control subjects (p less than 0.001). Total urinary coproporphyrin excretion was markedly increased in patients with Rotor's syndrome (332 +/- 86 mug/g creatinine) as compared to that in control subjects (p less than 0.001) or obligate heterozygotes (p less than 0.025). With respect to urinary coproporphyrin excretion, Rotor's syndrome and Dubin-Johnson syndrome are both inherited as autosomal recessive traits and are separate pathophysiologic entities. Study of rare but distinct inheritable disorders, such as these, provide insight into the functional dissociation of hepatic transport mechanisms.

Animals↗
PubMed1976

Ligandin and Z protein in binding of thyroid hormones by the liver.

Sephadex G-100 chromatography of rat liver supernatant after addition of [125I]T3 revealed four peaks of protein-bound radioactivity in the void volume, albumin, ligandin, and Z-containing regions, respectively. The peaks were identified by cochromatography of BSP and [125I]T3 and immonodiffusion with antiratligandin IgG and antirat Z IgG. Binding of [125I]T4 to rat liver supernatant occurred in void volume, albumin, and Z regions only. Studies in vivo reveal a pattern of [125I]T3 binding to rat liver supernatant fractions quantitatively different from that observed in vitro. [125I]T4 binding to liver supernatant fractions in vivo occurred in all four peaks. BSP or bilirubin added to liver supernatant decreased T3 and T4 binding by each fraction. Flavaspidic acid inhibited binding of T3 and T4 to albumin, ligandin, and Z protein. Phenobarbital pretreatment of rats increased binding of T3 by ligandin and of T4 by albumin-containing fractions. Circular dichroism studies with purified rat liver ligandin suggest that T3 and T4 bind competitively to the same site as does bilirubin; the association constants of T3 and T4 for ligandin are 10(6) and 10(5) M-1, respectively. T4 was bound only by purified ligandin and not by ligandin in liver supernatant. To determine whether unconjugated bilirubin interferes with hepatic uptake of T3, [125I]T3 was administered to icteric homozygous and phenotypically normal heterozygous Gunn rats. Hepatic uptake and supernatant binding [125I]T3 were significantly reduced in homozygous Gunn rats. Hepatic uptake of [125I]T3 was also reduced in vivo by infusion of BSP with or without flavaspidic acid. BSP infusion abolished [125I]T3 binding to ligandin; BSP and flavaspidic acid abolished binding to ligandin and Z. These observations suggest that ligandin and Z protein are thyroid hormone binding proteins in rat liver cytosol and may influence the net flux of iodothyronies from plasma into the liver.

Animals↗
PubMed1976

Effect of fasting on hepatic ligandin, Z protein, and organic anion transfer from plasma in rats.

The effect of fasting on the rate of disappearance from plasma of bromsulphthalein (BSP) and dibromsulphthalein (DBSP), the hepatic content of BSP, and the concentration of ligandin and Z protein, two hepatic organic anion-binding proteins, was studied in the rat. Fasting for 48 h decreased the plasma disappearance of BSP and DBSP and the hepatic content of BSP as well as the amount of ligandin and Z protein. Phenobarbital given prior to fasting partially prevented these changes. A method of quantitation of Z by radioimmunoassay is described. Discrepancies in Z quantiation by dye binding and immunological methods in fasted but not control rats suggest the presence of competitors for organic anion binding to Z in fasting as well as after phenobarbital administration. Results of studies of ligandin turnover during fasting suggest decreased synthesis and increased degradation of the protein. Similar events may be of pathogenetic importance in nonhemolytic unconjugated hyperbilirubinemia observed during fasting in man, horses, and other animals.

Animals↗