Chemical-induced liver injury

Cytotoxicity. The liver is the primary target organ for a variety of drugs and chemicals (Hasemen et ah, 1984 Farland et ah, 1985). The prevalence of drug-and chemical-induced liver injury is of concern because some xenobiotics can produce liver damage at dose levels that are magnitudes below that which causes cell death (Plaa, 1976). Environmental and commercial chemicals can increase this effect by as much as 100-fold (Plaa and Hewitt, 1982 Plaa, 1976). Studies of early cell injury caused by exposure to a toxicant can be undertaken easily in monolayer cultures of hepatocytes, whereas early cell injury is very difficult to assess in vivo. 

Chemical-induced liver injury is encountered in a variety of circumstances. Some natural toxins such as the peptides of Amanita phalloides, the pyrrolizidine alkaloids, the toxin of the cycad nut, and other plant toxins are hazards posed by the environment. Some mycotoxins are ingested unknowingly because of feed contamination due to climatic conditions favorable to fungal growth. Other circumstances of exposure to hepatotoxins include contamination of water supply with cyanobacterial toxins, which led to the tragic death of 60 patients in a hemodialysis clinic in Brazil in 1996 (Jochimsen et al, 1998). 

Chemical-induced liver injury is differentially modified by diabetes in murine type 1 diabetic models. Contrary to the enhanced hepatotoxicity in diabetic rats, diabetes in mice tends to protect animals from severe hepatotoxicity. It has been reported that the induction of diabetes in Swiss mice did not increase the susceptibility of mice to CCI4 hepatotoxicity as occurs in rats. Development of diabetes also protected mice from acetaminophen toxicity. Further studies also showed that streptozotocin-induced diabetic mice were substantially resistant to lethal doses... 

There are species differences for the individual bile acids. Cholic acid is the major primary bile acid in most species. Muricholic acid is a major bile acid in the rat that increases rapidly during cholestasis (Hofmann 1988). More experimental work is needed to analyze the patterns of individual bile acids after various forms of chemically induced liver injury to see if these profiles can provide better diagnosis. 

Plaa, G. L., and M. Charbonneau. 2001. Detection and evaluation of chemically induced liver injury. In Principles and methods of toxicology, 4th ed., ed. A. W. Hayes, pp. 1145-1187. Philadelphia Taylor Francis. 

Pritchard, D. H., M. G. Wright, S. Sulsh, and W. H. Butler. 1987. The assessment of chemically induced liver injury in rats. Journal of Applied Toxicology 7 229-236. 

Plaa GL, Traiger GJ, Hanasono GK, et al. 1975. Effect of alcohols on various forms of chemically induced liver injury. Alcohol Liver Pathol [Proc Int Symp Alcohol Drug Res] 225-244. 

Hepatotoxicity was reported in an elderly man who had been taking an herbal stimulant laxative for many years. The hepatotoxicity appeared shortly after the laxative was reformulated to contain boldo (Piscaglia et al. 2005). An animal study reported a protective effect of boldo against chemical-induced liver injury (Lanhers et al. 1991). 

Research in the last decade has focused on elucidating different mechanisms for chemical-induced liver injury. Investigators have attempted to understand the basis for such hepatic injury. The goal of this chapter is to provide a basic understanding of liver pathophysiology and to introduce the general concepts of liver injury. The chapter also describes a few examples of CWAs that can inflict liver damage. 

The best clinical evidence that BSEP is involved in hepatotoxicity is provided by human genetic studies which found four highly conserved non-synonymous mutations in two hepatobiliary transporters (BSEP and MDR3) that were specific for drug-induced liver injury [118]. Recently, a consortium of investigators identified a remarkable 82 different ABCBll mutations in 109 families that caused severe BSEP deficiency [119]. It is therefore expected that at least some of these genetic mutations and polymorphisms will put patients at an increased risk of drug-induced cholestasis. Does this justify the implementation of a simple BSEP inhibition screen for all new chemical entities The answer is not quite that simple. 

Xenobiotic-induced liver injury has become the most frequent cause of acute liver failure in humans in the USA and around the world, exceeding all other causes combined (Watkins and Seef, 2006). Owing to its detoxification mechanisms, the liver protects the individual against xenobiotic-induced injury. Certainly, the liver toxicity caused by chemical warfare agents is a potential area of concern. 

UlzmTun, E., Stephens, C., Crespo, E., Ruiz-CabeUo, F., Ruiz-Nunez, J., Saenz-L6pez, R, Moreno-Herrera, I., Robles-Diaz, M., Hallal, H., Moreno-Planas, J.M., Maria, R., Cabello, M.R., Lucena, M.I., and Andrade, R.J. (2013) Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury. Liver Int., 33, 1378-1385. 

Due to the aforementioned discrepancy in data availability (especially relevant to translation of toxic effect) and the fact that many clinical endpoints are multi-mechanistic, it is important to stress that each computational step should be well defined and model small steps, for example, a traditional quantitative structure-activity relationship (QSAR) approach based on chemical structure is probably relevant to distinguish hERG binders from nonbinders, but not relevant to model a small set of diverse compounds associated with a complex endpoint such as drug induced liver injury (DILI). A second important factor to consider when construchng in silico safety models is the intended use of the model, and the potential cost associated with false positives versus false negatives from the model. For instance, there is zero... 

Kadota, S.H., Hase, K., Basnet, P., Takahashi, T, Namba, T Protective effect of celosian, an acidic polysacchride on chemically and immmunologically induced liver injuries. Biol. Pharm. Bull. 19(4), 567-572 (1996)... 

Baker NC, Hemminger BM (2010) Mining connections between chemicals, proteins, and diseases extracted from Medline annotations. J Biomed Inform 43 510-519 Fourches D, Barnes JC, Day NC, Bradley R Reed JZ, Tropsha A (2010) Cheminformatics analysis of assertions mined from literature that describe drug-induced liver injury in different species. Chem Res Toxicol 23 171-183... 

A particular instance of iron overload being associated with liver injury, with free radicals again being implicated, is the hepatic porphyria and hepatocarcinoma induced by polyhalogenated aromatic chemicals. This is described separately below. 

Smith, A.G., Francis, J.E., Cabral, J.R.P., Carthew, P., M.M., M. and Stewart, F.P. (1989). Iron-enhancement of the hep-tatic porphyria and cancer induced by environmental poly-halogenated aromatic chemicals. In Free Radicals in the Pathogenesis of Liver Injury (eds. G. Poli, K.H. Cheeseman, M.U. Dianzani and T.F. Slater) pp. 203-216. Peigamon Press, Oxford. 

Liver disease may decrease hepatic metabolism resulting in enhanced responses to parent chemicals however, for many compounds, metabolism is only slightly impaired in moderate to severe liver disease. Disease-induced alterations in clearance and volume of distribution often act in opposite directions with respect to their effect on half-life. Bioavailability may be markedly increased in liver disease with portal/systemic anastomosis (the connection of normally separate parts so they intercommunicate) so that orally administered chemicals bypass hepatic first-pass metabolism. Altered receptor sensitivity has been observed for some chemical substances in liver cirrhosis. When liver tissue repair is inhibited by chemical co-exposure, even an inconsequential level of liver injury may lead to fulminating liver failure from a nonlethal exposure of hepatotoxic-ants. (Several articles, as reviewed by Dybing and Spderlund 1999.)... 

---