Ligandin: an adventure in liverland

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.