Liver Diseases
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
These tests provide an indication of various hepatic functions necessary for diagnosis, and they are generally useful guides to therapy. These biochemical tests demonstrate functional disturbances of the liver, and therefore they are based on specific functions. Accordingly, they can be grouped into classes: (1) tests on excretory function: serum bilirubin determinations, measurement of bile derivatives, and dye excretion tests such as bromsulphthalein; (2) tests on metabolic function and indirect indicators of synthesis: serum proteins, flocculation tests, serum enzymes, serum cholesterol, and prothrombin time; (3) tests on biotransformation of various compounds; and (4) tests on detoxication mechanisms. The latter group contains many noninvasive methods.44,63,64,384,471,604
Aspects of Bilirubin Transport
Karel P. M. Heirwegh, Stanley B. Brown in Bilirubin, 1982
In the rat, studies of the subcellular distribution of injected radiolabeled bilirubin revealed that the major part of hepatic bilirubin resides in the cytosol.62,63 In 1967, bilirubin-binding proteins were discovered in rat liver cytosol.64,65 Electrophoresis and centrifugation in density gradients demonstrated two groups of binding proteins of 4.0 and 1.6 S, respectively, and thus different from albumin (4.3 S) (Figure 1).8,66 In the homozygous Gunn rat, they respectively carry 60 to 70% (4.0 S) and 30 to 40% (1.6 S) of the pigment. Using gel filtration on Sephadex® G-75, bromsulphthalein (BSP) and bilirubin added to cytosol were recovered in three protein fractions, called X, Y, and Z.67 The X-fraction is an artifact.68 The Y-fraction (46,000 Da) and the Z-fraction (about 13,000 Da) correspond to the 4.0 and 1.6 S fractions, respectively. The Y- and Z-fractions, which are known collectively as organic anion-binding proteins, also bind anionic dyes such as indocyanine green (ICG), Rose Bengal and Cholangiographie contrast media.69 All these compounds are hepatophilic aromatic anions and also bind to serum albumin with varying affinity.26
Fusidate Sodium
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Because of the steroid structure of fusidate sodium, it was thought that this drug may possibly have some metabolic effects unrelated to its antibacterial activity. Wynn (1965) showed that no significant metabolic changes were associated with fusidate sodium administration. It had a mild protein catabolic effect, it lowered urinary calcium excretion, and it also caused mild temporary impairment of bromsulphthalein excretion by the liver. It is conceivable that the latter finding may have some relation to the ability of the drug to impair liver function. Human leukocytes incubated with fusidate sodium show markedly depressed migration (Forsgren and Schmeling, 1977). The clinical significance of this observation is unknown.
Diagnostic criteria and contributors to Gilbert’s syndrome
Published in Critical Reviews in Clinical Laboratory Sciences, 2018
Karl-Heinz Wagner, Ryan G. Shiels, Claudia Anna Lang, Nazlisadat Seyed Khoei, Andrew C. Bulmer
Interestingly, Rotor syndrome is associated with elevated TB and DBIL; it is a consequence of reduced DBIL transport into hepatocytes, which is caused by reduced expression of organic anion transporters OATP1B1 or OATP1B3 in the basolateral membrane of hepatocytes [78]. An increased DBIL suggests either Rotor or Dubin-Johnson syndrome. Rotor syndrome can be differentiated from Dubin-Johnson syndrome by observing delayed plasma clearance of bromsulphthalein, increased urinary excretion of coproporphyrins, and a lack of granular hepatocyte pigmentation [67].
Efflux proteins at the blood–brain barrier: review and bioinformatics analysis
Published in Xenobiotica, 2018
Massoud Saidijam, Fatemeh Karimi Dermani, Sareh Sohrabi, Simon G. Patching
The human tissue with the highest OATP1A2 mRNA expression is the brain (Cheng et al., 2012). OATP1A2 is primarily located at the luminal side of the blood–brain barrier and is therefore a potential target for drug delivery to the brain and central nervous system. Indeed, the expression of OATP1A2 mRNA in the human brain is comparable with that of BCRP and OATP2B1 and much higher than that of P-gp (Liu et al., 2015). One study has demonstrated how protein kinase C regulates the internalisation and function of OATP1A2, whereby protein kinase C activation decreased the transport function of OATP1A2 in a time- and concentration-dependent manner. It is suggested that this effect of protein kinase C is partly mediated by clathrin-dependent pathways (Zhou et al., 2011). It has also been demonstrated that the PDZ-domain containing proteins PDZK1 and NHERF1 regulate the transport function of OATP1A2 by modulating protein internalisation via a clathrin-dependent pathway and by enhancing protein stability (Zheng et al., 2014). Endogenous substrates of OATP1A2 include bile acids, bilirubin, PGE2, steroid conjugates and thyroid hormones, and other substrates include antibiotics, anticancer drugs, beta blockers, bromsulphthalein, fexofenadine, fluoroquinolones, HIV protease inhibitors, microcystin-LR, ouabain, rosuvastatin and Talinolol. The hydrophilic anti-migraine triptans have also been identified as substrates for OATP1A2 (Cheng et al., 2012). Inhibitors of OATP1A2 include rifampicin, rifamycin and naringin. Using an in vitro system for OATP1A2 expression in Madin-Darby canine kidney II cells, OATP1A2-mediated uptake of zolmitriptan, rosuvastatin and fexofenadine across monolayers increased with increasing OATP1A2 protein expression, and OATP1A2 counteracted P-gp efflux for the co-substrates zolmitriptan and fexofenadine (Liu et al., 2015). Such in vitro models are important for studying competing transport processes at the blood–brain barrier with implications for delivery of drugs to the brain and central nervous system.