Abstract
The hepatic uptake of bilirubin (BR), indocyanine green (ICG), and sulfobromophthalein (BSP) was studied in 350 anesthetized Sprague-Dawley rats by determining the initial plasma disappearance rate (V) of various doses of unlabeled ICG, or of tracer quantities of [3H]BR or [35S]BSP injected into the jugular vein simultaneously with varying amounts of unlabeled BR or BSP. Similar studies were also performed involving the simultaneous injection of potential inhibitors of hepatic uptake. The results indicate that: (a) hepatic uptake determined by direct tissue measurement could be accurately estimated from the plasma disappearance data; (b) saturation of hepatic uptake with increasing dose was readily demonstrated for each of these three organic anions, and in each instance a plot of V versus dose took the form of a rectangular hyperbola analyzable in terms of Michaelis-Menten kinetics; (c) for BR, the saturable uptake process showed a Vmax more than 100 times the normal net transfer rate from plasma to bile; (d) hepatic uptake of BR, BSP, and ICG showed relatively selective, mutually competitive inhibition; glycoholic acid did not inhibit hepatic uptake of any of these substances; and (e) "counter-transport" could be demonstrated for each of the three test substances. These data are compatible with the existence of a carrier-mediated transport process for hepatic uptake of each of these three organic anions and clarify the relationship of hepatic BR uptake to its overall transport from plasma to bile.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- BERMAN M. The formulation and testing of models. Ann N Y Acad Sci. 1963 May 10;108:182–194. doi: 10.1111/j.1749-6632.1963.tb13373.x. [DOI] [PubMed] [Google Scholar]
- BILLING B. H., MAGGIORE Q., CARTTER M. A. HEPATIC TRANSPORT OF BILIRUBIN. Ann N Y Acad Sci. 1963 Dec 30;111:319–325. doi: 10.1111/j.1749-6632.1963.tb36974.x. [DOI] [PubMed] [Google Scholar]
- Berk P. D., Blaschke T. F., Waggoner J. G. Defective bromosulfophthalein clearance in patients with constitutional hepatic dysfunction (Gilbert's syndrome). Gastroenterology. 1972 Sep;63(3):472–481. [PubMed] [Google Scholar]
- Berk P. D., Howe R. B., Bloomer J. R., Berlin N. I. Studies of bilirubin kinetics in normal adults. J Clin Invest. 1969 Nov;48(11):2176–2190. doi: 10.1172/JCI106184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Black M., Billing B. H., Heirwegh K. P. Determination of bilirubin UDP-glucuronyl transferase activity in needle-biopsy specimens of human liver. Clin Chim Acta. 1970 Jul;29(1):27–35. doi: 10.1016/0009-8981(70)90216-0. [DOI] [PubMed] [Google Scholar]
- Blaschke T. F., Berk P. D., Scharschmidt B. F., Guyther J. R., Vergalla J. M., Waggoner J. G. Crigler-Najjar syndrome: an unusual course with development of neurologic damage at age eighteen. Pediatr Res. 1974 May;8(5):573–590. doi: 10.1203/00006450-197405000-00006. [DOI] [PubMed] [Google Scholar]
- Blaschke T. F., Elin R. J., Berk P. D., Song C. S., Wolff S. M. Effects of induced fever on sulfobromophthalein kinetics in man. Ann Intern Med. 1973 Feb;78(2):221–226. doi: 10.7326/0003-4819-78-2-221. [DOI] [PubMed] [Google Scholar]
- GORESKY C. A. INITIAL DISTRIBUTION AND RATE OF UPTAKE OF SULFOBROMOPHTHALEIN IN THE LIVER. Am J Physiol. 1964 Jul;207:13–26. doi: 10.1152/ajplegacy.1964.207.1.13. [DOI] [PubMed] [Google Scholar]
- GORESKY C. A. THE HEPATIC UPTAKE AND EXCRETION OF SULFOBROMOPHTHALEIN AND BILIRUBIN. Can Med Assoc J. 1965 Apr 17;92:851–857. [PMC free article] [PubMed] [Google Scholar]
- Gisselbrecht C., Berk P. D. Failure of phenobarbital to increase bilirubin production in the rat. Biochem Pharmacol. 1974 Oct 15;23(20):2895–2905. doi: 10.1016/0006-2952(74)90064-1. [DOI] [PubMed] [Google Scholar]
- Grodsky G. M., Kolb H. J., Fanska R. E., Nemechek C. Effect of age of rat on development of hepatic carriers for bilirubin: a possible explanation for physiologic jaundice and hyperbilirubinemia in the newborn. Metabolism. 1970 Mar;19(3):246–252. doi: 10.1016/0026-0495(70)90059-4. [DOI] [PubMed] [Google Scholar]
- HEINZ E. Kinetic studies on the influx of glycine-1-C14 into the Ehrlich mouse ascites carcinoma cell. J Biol Chem. 1954 Dec;211(2):781–790. [PubMed] [Google Scholar]
- HUNTON D. B., BOLLMAN J. L., HOFFMAN H. N., 2nd The plasma removal on indocyanine green and sulfobromophthalein: effect of dosage and blocking agents. J Clin Invest. 1961 Sep;40:1648–1655. doi: 10.1172/JCI104387. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Habig W. H., Pabst M. J., Fleischner G., Gatmaitan Z., Arias I. M., Jakoby W. B. The identity of glutathione S-transferase B with ligandin, a major binding protein of liver. Proc Natl Acad Sci U S A. 1974 Oct;71(10):3879–3882. doi: 10.1073/pnas.71.10.3879. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heirwegh K. P., Van Hees G. P., Leroy P., Van Roy F. P., Jansen F. H. Heterogeneity of bile pigment conjugates as revealed by chromatography of their ethyl anthranilate azopigments. Biochem J. 1970 Dec;120(4):877–890. doi: 10.1042/bj1200877. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Howe R. B., Berk P. D., Bloomer J. R., Berlin N. I. Preparation and properties of specifically labeled radiochemically stable 3H-bilirubin. J Lab Clin Med. 1970 Mar;75(3):499–502. [PubMed] [Google Scholar]
- Kamisaka K., Listowsky I., Arias I. M. Circular dichroism studies of Y protein (ligandin), a major organic anion binding protein in liver, kidney, and small intestine. Ann N Y Acad Sci. 1973 Nov 26;226:148–153. doi: 10.1111/j.1749-6632.1973.tb20477.x. [DOI] [PubMed] [Google Scholar]
- LEEVY C. M., BENDER J. PHYSIOLOGY OF DYE EXTRACTION BY THE LIVER: COMPARATIVE STUDIES OF SULFOBROMOPHTHALEIN AND INDOCYANINE GREEN. Ann N Y Acad Sci. 1963 Dec 30;111:161–176. doi: 10.1111/j.1749-6632.1963.tb36956.x. [DOI] [PubMed] [Google Scholar]
- LEWIS A. E., GOODMAN R. D., SCHUCK E. A. Organ blood volume measurements in normal rats. J Lab Clin Med. 1952 May;39(5):704–710. [PubMed] [Google Scholar]
- Leevy C. M., Smith F., Longueville J., Paumgartner G., Howard M. M. Indocyanine green clearance as a test for hepatic function. Evaluation by dichromatic ear densitometry. JAMA. 1967 Apr 17;200(3):236–240. [PubMed] [Google Scholar]
- Levi A. J., Gatmaitan Z., Arias I. M. Deficiency of hepatic organic anion-binding protein as a possible cause of non-haemolytic unconjugated hyperbilirubinaemia in the newborn. Lancet. 1969 Jul 19;2(7612):139–140. doi: 10.1016/s0140-6736(69)92444-1. [DOI] [PubMed] [Google Scholar]
- Levi A. J., Gatmaitan Z., Arias I. M. Deficiency of hepatic organic anion-binding protein, impaired organic amnion uptake by liver and "physiologic" jaundice in newborn monkeys. N Engl J Med. 1970 Nov 19;283(21):1136–1139. doi: 10.1056/NEJM197011192832104. [DOI] [PubMed] [Google Scholar]
- Levi A. J., Gatmaitan Z., Arias I. M. Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anions. J Clin Invest. 1969 Nov;48(11):2156–2167. doi: 10.1172/JCI106182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Levine M., Oxender D. L., Stein W. D. The substrate-facilitated transport of the glucose carrier across the human erythrocyte membrane. Biochim Biophys Acta. 1965 Sep 27;109(1):151–163. doi: 10.1016/0926-6585(65)90099-3. [DOI] [PubMed] [Google Scholar]
- Levine R. I., Reyes H., Levi A. J., Gatmaitan Z., Arias I. M. Phylogenetic study of organic anion transfer from plasma into the liver. Nat New Biol. 1971 Jun 30;231(26):277–279. doi: 10.1038/newbio231277a0. [DOI] [PubMed] [Google Scholar]
- Litwack G., Ketterer B., Arias I. M. Ligandin: a hepatic protein which binds steroids, bilirubin, carcinogens and a number of exogenous organic anions. Nature. 1971 Dec 24;234(5330):466–467. doi: 10.1038/234466a0. [DOI] [PubMed] [Google Scholar]
- Mawe R. C., Hempling H. G. The exchange of C14 glucose across the membrane of the human erythrocyte. J Cell Physiol. 1965 Aug;66(1):95–103. doi: 10.1002/jcp.1030660110. [DOI] [PubMed] [Google Scholar]
- Plotz P. H., Berk P. D., Scharschmidt B. F., Gordon J. K., Vergalla J. Removing substances from blood by affinity chromatography. I. Removing bilirubin and other albumin-bound substances from plasma and blood with albumin-conjugated agarose beads. J Clin Invest. 1974 Mar;53(3):778–785. doi: 10.1172/JCI107616. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Quarfordt S. H., Hilderman H. L., Valle D., Waddell E. Compartmental analysis of sulfobromophthalein transport in normal patients and patients with hepatic dysfunction. Gastroenterology. 1971 Feb;60(2):246–255. [PubMed] [Google Scholar]
- Reyes H., Levi A. J., Gatmaitan Z., Arias I. M. Organic anion-binding protein in rat liver: drug induction and its physiologic consequence. Proc Natl Acad Sci U S A. 1969 Sep;64(1):168–170. doi: 10.1073/pnas.64.1.168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reyes H., Levi A. J., Gatmaitan Z., Arias I. M. Studies of Y and Z, two hepatic cytoplasmic organic anion-binding proteins: effect of drugs, chemicals, hormones, and cholestasis. J Clin Invest. 1971 Nov;50(11):2242–2252. doi: 10.1172/JCI106721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosenberg T., Wilbrandt W. Carrier transport uphill. I. General. J Theor Biol. 1963 Sep;5(2):288–305. doi: 10.1016/0022-5193(63)90065-1. [DOI] [PubMed] [Google Scholar]
- Silverman M., Goresky C. A. A unified kinetic hypothesis of carrier mediated transport: its applications. Biophys J. 1965 Jul;5(4):487–509. doi: 10.1016/S0006-3495(65)86731-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Van Roy F. P., Meuwissen J. A., De Meuter F., Heirwegh K. P. Determination of bilirubin in liver homogenates and serum with diazotized p-iodoaniline. Clin Chim Acta. 1971 Jan;31(1):109–118. doi: 10.1016/0009-8981(71)90367-6. [DOI] [PubMed] [Google Scholar]
- WEBER A. P., SCHALM L. Quantitative separation and determination of bilirubin and conjugated bilirubin in human serum. Clin Chim Acta. 1962 Nov;7:805–810. doi: 10.1016/0009-8981(62)90063-3. [DOI] [PubMed] [Google Scholar]