Ligandin: An adventure in Liverland

Abstract

Ligandin is an abundant soluble protein which has a t 1/2 of 2--3 days, is induced by many drugs and chemicals, and is stabilized in the absence of thyroid hormone. The protein is strategically concentrated in cells associated with transport and detoxification of many endogenous ligands, such as bilirubin, and exogenous ligands, such as drugs and chemicals. The protein is a dimer in rat liver. Whether the dimer is a primary gene product or at least two genes are involved is not known. The protein has broad, low affinity catalytic activity as a GSH-S-transferase for many ligands having electrophilic groups and hydrophobic domains. It catalyzes formation of GSH conjugates, non-covalently binds some ligands prior to their biotransformation or excretion in bile, and covalently binds other ligands, such as activated carcinogens. Recent studies include the possible role of ligandin in chemical carcinogenesis, diagnosis of inflammatory and neoplastic disease of the liver and kidney, and participation in intracellular transport. Although some of the roles that have been outlined are speculative, any single function is important. The GSH-S-transferases are primitive enzymes and non-specific binding proteins but "it is precisely their simplistic design that allows such protean serviceability". Ligandin illustrates a group of hepatic disposal mechanisms which involve bulk transport of ligands. Although specific uptake and transport mechanisms have been described for several hormones which enter the hepatocyte in small quantities and regulate intermediary metabolism and, possibly, cell maturation, bulk transport of ligands into, through and out of the liver involves mechanisms which accomodate many metabolites, drugs and chemicals of diverse structure. The liver is bathed in sewage which contains what we ingest or are injected with and potentially toxic products of intestinal microorganisms. The chemical formulas of the many substances which are metabolized by the liver provide a horror show of potentially reactive and toxic metabolites, mutagens and carcinogens. Despite this alimentary "Love Canal", we and our livers do remarkably well. These hepatic disposal mechanisms, as exemplified by ligandin, evolved in ancient times. They are present, albeit sluggishly, in insects and ancient elasmobranchs. Hepatic uptake and removal mechanisms of high capacity, modest affinity and broad substrate range permit us to live in what has probably always been a threatening world.

Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure

“…The reason for this change is not clear, but it is unlikely to be due to reduced content of binding proteins because there was no difference in either cytosol or Y-fraction protein levels between control and ARF rats. About 80% of the binding capacity of the Y fraction is due to a single protein called ligandin (Arias et al, 1980). Ligandin is capable of binding a large number of structurally diverse ligands (Litwack et al, 1971;Ketley et al, 1975;Magos et al, 1985) and in this respect it is similar to albumin.…”

“…We have mentioned previously that reduced binding to liver cytosol proteins may account for the altered uptake of dyes such as DBSP in ARF. Ligan- OCy din is a major intracellular binding protein (Arias et al, 1980) and it may aid net hepatic uptake by restricting efflux of its ligands from the hepatocyte into plasma (Wolkoff et al, 1979a). Thus a decrease in the binding capacity of this protein could facilitate loss of dye from the cell, so reducing net uptake.…”

Gene deletion and partial deficiency of the glutathione S‐transferase (ligandin) system in man

“…These results also have significance in the evaluation of ligandinaemia associated with liver disease [4][5][6][7][8][9]. The presence of a common null allele which significantly affects the level of glutathione S-transferase/ligandin in liver is likely to influence the degree of ligandinaemia which occurs in various hepatic disorders.…”

“…More recently, ligandinaemia has been reported in a number of inflammatory and neoplastic liver diseases, including viral and chronic hepatitis, cirrhosis and primary hepatocarcinoma [4][5][6][7]. These observations have prompted the suggestion that ligandinaemia may well provide a further means of evaluating liver damage and be of diagnostic value in cases of primary liver cell cancer [8,9].…”

Ultrastructural, Protein, and Lipid Changes in Liver Associated with Chlordecone Treatment of Mice

“…Several of these carrier proteins have other, very different functions in addition to acting as binding proteins. For example, ligandin, or glutathione transferase B, catalyzes the conjugation of glutathione to electrophilic compounds (Arias et al, 1980), sterol carrier proteins function in cholesterol synthesis from squalene (Clarke and Armstrong, 1989), and cytochrome P-450 isozymes can act as nonenzymic sequestration proteins (Poland et al, 1989a;Aust, 1987, 1989). Cytosolic lipoprotein complexes may have a role in the transport of benzo [a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Lesca et al, 1987;Soues et al, 1989a,b).…”