Hepatotoxicants

Bulera SJ, Eddy SM, Ferguson E, Jat-koe TA, Reindel JF, Bleavins MR et al. RNA expression in the early characterization of hepatotoxicants in Wistar rats by high-density DNA microarrays. Hepatology 2001 33 1239-1258. 

Oikari, A. and B. Jimenez. 1992. Effects of hepatotoxicants on the induction of microsomal monooxygenase activity in sunfish liver by beta-naphthoflavone and benzo[a]pyrene. Ecotoxicol. Environ. Safety 23 89-102. 

Recently we have evaluated several exogenous and endogenous tests of liver function in rainbow trout following intoxication by the model hepatotoxicant CCl. The results of these studies indicate that elevated plasma activity of the enzyme glutamate-pyruvate transaminase (GPT) is the most sensitive endogenous index of... 

Wright PB, Moore L. 1991. Potentiation of the toxicity of model hepatotoxicants by acetaminophen. Toxicol AppI Pharmacol 109 327-335. 

Ulric RG, Rockett JC, Gibson GG et al. Overview of an interlaboratory collaboration on evaluating the effects of model hepatotoxicants on hepatic gene expression. Environ Health Perspect 2004 112 423 27. 

Dimethylnitrosamine is both a hepatic carcinogen and a hepatotoxicant. Does either effect require metabolism, and if so, what is (are) the metabolite(s) responsible for the carcinogenicity ... 

The definition of a poison, or toxicant, also involves a qualitative biological aspect because a compound, toxic to one species or genetic strain, may be relatively harmless to another. For example, carbon tetrachloride, a potent hepatotoxicant in many species, is relatively harmless to the chicken. Certain strains of rabbit can eat Belladonna with impunity while others cannot. Compounds may be toxic under some circumstances but not others or, perhaps, toxic in combination with another compound but nontoxic alone. The methylenedioxyphenyl insecticide synergists, such as piperonyl butoxide, are of low toxicity to both insects and mammals when administered alone but are, by virtue of their ability to inhibit xenobiotic-metabolizing enzymes, capable of causing dramatic increases in the toxicity of other compounds. 

The specific organ toxicity of chemicals also exhibits wide species differences. Carbon tetrachloride, a highly potent hepatotoxicant, induces liver damage in many species,... 

Mechanisms such as conjugation of the reactive chemical with glutathione are protective mechanisms that exist within the cell for the rapid removal and inactivation of many potentially toxic compounds. Because of these interactions, cellular toxicity is a function of the balance between the rate of formation of reactive metabolites and the rate of their removal. Examples of these interactions are presented in the following discussions of specific hepatotoxicants. 

Chloroform is a common industrial organic solvent that can be a hepatotoxicant or a nephrotoxicant in both humans and animals. As a nephrotoxicant it is both species and gender dependent. For example, following chloroform administration male mice develop primarily kidney necrosis whereas female develop liver necrosis. 

These radical species, along with others produced from their subsequent reactions, can react with biomolecules, such as proteins and DNA. The most damaging such reaction is lipid peroxidation, a process that involves the attack of chemically active species on unsaturated lipid molecules, followed by oxidation of the lipids through a free radical mechanism. It occurs in the liver and is a main mode of action of some hepatotoxicants, which can result in major cellular damage. The mechanism of lipid peroxidation may involve abstraction of the methylene hydrogens attached to doubly bonded carbon atoms in lipid molecules ... 

The regional expression of xenobiotic metabolizing enzymes determines the zone-specific localization of toxicant damage. Many hepatotoxicants elicit perivenous damage because CYPs are preferentially localized in centrilobular hepatocytes. For example, acetaminophen causes hepatotoxicity because the reactive... 

Quiescent, perisinusoidal hepatic stellate cells (HSC) accumulate retinoids (vitamin A and its metabolites) in large cytoplasmic droplets and store about 80% of body s retinoids. However, these cells also express the muscle protein desmin and become activated to myofibroblasts upon exposure to hepatotoxicants. Activated HSC synthesize extracellular matrix proteins, especially when stimulated by cytokines and growth factors (see Section 28.4.2). 

Classification of chemically induced hepatotoxicity is primarily based upon pattern of incidence and histopathological morphology. Intrinsic hepatotoxic drugs demonstrate a broad incidence, dose-response relationship and will usually give similar results in humans and experimental animals. The incidence of liver damage from idiosyncratic hepatotoxicants is limited to susceptible individuals and results from hypersensitivity reactions or unusual metabolic conversions that can occur due to polymorphisms in drug metabolism genes (see Chapters 11 and 13). 

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