Mechanisms of Hepatotoxicity

Chemically induced cell injury can be thought of as involving a series of events occurring in the affected animal and often in the target organ itself  

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Thompson, D. C. Perera, K. London, R. Studies on the mechanism of hepatotoxicity of 4-methylphenol(/j-cresol)—effects of deuterium labeling and ring substitution. Chem.-Biol. Interact. 1996, 101, 1-11. 

Comparative Toxicokinetics. Metabolic pathways and mechanisms of hepatotoxicity of carbon tetrachloride have been the subject of many studies in intact animals and in vitro, and are therefore better understood than for many other chemicals. However, there are apparently no data on metabolism of carbon tetrachloride in humans. It would be valuable to conduct in vitro experiments with human liver samples and hepatocytes to determine whether metabolic pathways and toxic metabolites are similar to those found in animals. It would also be beneficial to identify an animal model in which MFO systems develop in uteroas they do in the human fetus. 

The mechanism of hepatotoxicity is therefore currently unclear. It has been suggested that lipid peroxidation is responsible rather than covalent binding to protein. Arylation of other low molecular weight nucleophiles such as coenzyme A and pyridine nucleotides also occurs and may be involved in the toxicity. Bromobenzene is known to cause the inhibition or inactivation of enzymes containing SH groups. It also causes increased breakdown of phospholipids and inhibits enzymes involved in phospholipid synthesis. Arylation of sites on... 

The most direct mechanism of hepatotoxicity is through specific interaction of a chemical with a key cellular component and consequential modulation of its function. More common mechanisms, however, involve secondary effects of toxicant interaction. These include depletion of cellular molecules, such as ATP and GSH free radical and oxidant damage, in particular to membrane lipids covalent binding of reactive metabolites to critical cellular molecules and collapse of regulatory ion gradients. The following discussion will highlight how these cellular and molecular mechanisms contribute to specific types of chemically induced hepatic lesions. 

Romagnnolo, J., Sadowskl, D.C., Lalor, E., Jewell, L., Thomson, AJ3.R. Cholestatic hepatocellular injury with azathioprine A case report and review of the mechanisms of hepatotoxicity. Can. J. Gastroenterol. 1998 12 479 -483... 

Because of the rare and unpredictable nature of hepatobihary reactions to terbinafine, the mechanism of hepatotoxicity has been hypothesized to be either immunological or metabolically mediated. A potentially toxic reactive metabolite of terbinafine, 7,7-dimethylhept-2-ene-4-jmal (TBF-A), the A-dealkylation product of terbinafine, has been identified in vitro (43). The authors speculated that this allylic aldehyde metabolite, formed by hver enzymes and conjugated with glutathione, would be transported across the canalicular membrane of hepatocytes and concentrated in the bile. The reactive monoglutathione conjugate could bind to hepatobiliary proteins and cause direct toxicity. Alternatively, it could modify canahcular proteins and lead to an immune-mediated reaction, causing cholestatic dysfunction. 

With the loss of bromide ion, mediated by cytochrome P450 enzyme in the liver, the trichlorocarbon free radical is responsible for lipid peroxidation, which is the predominant mechanism of hepatotoxicity ... 

Niacin-induced vasodilation is believed to be mediated by prostaglandins. The mechanism of hepatotoxicity associated with niacin use is unknown. 

T, Vinken M, Weiss TS, Widera A, Woods CG, Xu JJ, Yarborough KM, Hengstler JG (2013) Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepato-cyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 87(8) 1315-1530... 

Trazodone therapy has been associated with several cases of idiosyncratic hepatotoxicity (see Chapter 10). Although the mechanism of hepatotoxicity remains unknown, the generation of an iminoquinone, an epoxide reactive metabolite or both may play a role in the initiation of trazodone-mediated hepatotoxicity (Fig. 

Nefazodone is a phenylpiperazine antidepressant structurally related to trazodone, but it differs pharmacologically from trazodone, the SSRIs, the MAOIs, and the TCAs (Fig. 21.22). When compared with trazodone, nefazodone displays approximately twice the affinity potency for SERT. Nefazodone therapy, however, was associated with life-threatening cases of idiosyncratic hepatotoxicity, and as a result, nefazodone was withdrawn from both the North American and European markets in 2003. The mechanism of hepatotoxicity remains unknown, but nefazodone, being structurally similar to trazodone (Fig. 21.23), is metabolized to p-hydroxynefazodone, m-CPP, and phenoxyethyltriazoledione. In turn, p-hydroxynefazodone is thought to be oxidized to an iminoquinone and/or an epoxide reactive metabolite, which may play a role in the initiation of nefazodone-mediated hepatotoxicity (76). 

Fromenty B, Pessayre D (1995) Inhibition of mitochondrial P-oxidation as a mechanism of hepatotoxicity. Pharmacol Ther 67 101-154... 

These data supported the hypothesis that acetaminophen-induced liver toxicity is mediated by covalent binding to critical proteins. In an attempt to further understand the mechanism of hepatotoxicity of acetaminophen, specific proteins to which acetaminophen was covalently bound were isolated and sequenced by our laboratory and by Cohen s laboratory (Cohen et al. 1997). The proteins that were identified by this approach were glutamine synthase, glutamate dehydrogenase,... 

A review of 69 published and unpublished case reports of black cohosh-associated hepatotoxicity indicated that there was an excluded, unlikely, unrelated, or unassess-able causality for black cohosh in 68 of 69 cases and "little, if any, supportive evidence for a significant hepatotoxic risk of black cohosh" (Teschke et al. 2009). Although one animal study on black cohosh rhizome has identified a biologically plausible mechanism of hepatotoxicity at high dose levels (Liide et al. 2007), no changes in liver enzyme levels have been observed in several human studies (Bai et al. 2007 Nasr and Nafeh 2009 Osmers et al. 2005 van Breemen et al. 2009). Healthcare practitioners and consumers should be aware of the possible association between products containing black cohosh and hepatotoxicity. 

In this text, the contraindication for use in pregnancy is based on concerns regarding the recent cases of hepatotoxicity reported in association with noni use, as the implications of these case reports and possible mechanisms of hepatotoxicity have yet to be fully understood. 

The specific mechanism of hepatotoxicity of many solvents are unknown, however, the knowledge have been gathered from experimental studies now available for the reader for review. 

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