Induced Liver Toxicity

TABLE 16.2 Classification of Drug-Induced Liver Toxicity 

Nonspecific hepatitis with cholestasis (chlorpromazine type) 

A pattern of liver necrosis similar to that caused by bromobenzene is observed in patients who ingest massive doses of acetaminophen (Table 16.2). This toxic reaction also has been produced experimentally in mice and rats and is thought to occur in two phases. An initial metabolic phase in which acetaminophen is converted to a reactive iminoquinone metabolite is followed by an oxidation phase in which an abrupt increase in mitochondrial permeability, termed mitochondrial permeability transition (MPT), leads to the release of superoxide and the generation of oxidizing nitrogen and peroxide species that result in hepatocellular necrosis (13, 14). 

FIGURE 16.5 Metabolism of bromobenzene (1) to a chemically reactive epoxide (arene oxide) metabolite (2) that can then either bind covalently to nearby macro-molecules, be scavenged by glutathione (GSH) (4) and be further metabolized 7), or be converted nonenzymatically or by epoxide hydrolase to stable hydroxylated metabolites 5, 8). 

Finally/ there is evidence that Kupffer cells are a source of the anti-inflammatory cytokine interleukin-10 (IL-10) that may play an important protective role by minimizing formation of reactive nitrogen species when superoxide is released following MPT (24). Pro-inflammatory cytokines (e.g./ macrophage migration inhibitory factor) may exacerbate hepatocellular necrosiS/ whereas chemokines (e.g./ monocyte chemoattractant protein-1) appear to reduce the extent of hepatotoxicity and facilitate eventual hepatocyte regeneration in surviving patients (13). 

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As discussed in Section 2.3.3, the mechanism of chloroform-induced liver toxicity may involve metabolism to the reactive intermediate, phosgene, which binds to lipids and proteins of the endoplasmic reticulum, lipid peroxidation, or depletion of GSH by reactive intermediates. Because liver toxicity has been observed in humans exposed to chloroform levels as low as 2 ppm in the workplace and in several animal species after inhalation and oral exposure, it is possible that liver effects could occur in humans exposed to environmental levels, to levels in drinking water, or to levels found at hazardous waste sites. 

Relative importance of covalent binding and lipid peroxidation in carbon tetrachloride-induced liver toxicity role of cell calcuim, protein and phospholipid degradation development of treatments/ antidotes. 

Thiamine is given for alcohol-induced liver toxicity (to prevent Wernicke s encephalopathy). 

Dnrnpt S, Josserand RN, Sibille M, Durieu I. Acute, recurrent fosfomycin-induced liver toxicity in an adult patient with cystic fibrosis. Scand J Infect Dis 2001 33(5) 391-2. 

Hui CK, Yuen MF, Ng lO, Tsang KW, Fong GC, Lai CL. Low molecular weight heparin-induced liver toxicity. J Clin Pharmacol 2001 41(6) 691. ... 

Prior hepatitis B infection may have predisposed this patient to labetalol-induced liver toxicity. 

Staerkel P, Horsmans Y. Meloxicam-induced liver toxicity. Acta Gastroenterol Belg 1999 62(2) 255-6. 

Concomitant treatment with other hepatotoxic agents can predispose to phenylbutazone-induced liver toxicity. 

Martines G, Butturini L, Menozzi I, Restori G, Boiardi L, Bernardi S, Baldassarri P. Amikacin-induced liver toxicity correlations between biochemical indexes and ultrastruc-tural features in an experimental model. Rev Med Univ Navarra 1988 32(l) 41-5. 

Temple RJ. Hepatotoxicity through the years impact on the FDA. Paper presented at Drug-Induced Liver Toxicity, Silver Spring, Maryland 2001. 

Wang T, Shankar K, Ronis MJ, Mehendale HM. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Crit Rev Toxicol. 2007 37(5) 413-459. 

Hoet P, Buchet JP, Sempoux C, et al. Potentiation of 2,2-dichloro-1,1,1 -trif-luoro (HCFC 123) induced liver toxicity by ethanol in guinea-pigs. Arch Toxicol2002 76(12) 707 14. 

Amacher DE (2010) The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity. Toxicol Appl Pharmacol 245 (1) 134-142. doi 10.1016/j.taap.2010.02.011... 

Ethanol, when given orally to mice at doses of 0.125-2.0 g/kg, potentiated both the lethality and behavioral effects (inverted screen test) of inhaled 1,1,1-trichloroethane at concentrations ranging from = 200 to 10,000 ppm (Woolverton and Balster 1981). In another study, a 3-day pretreatment of mice with ethanol enhanced 1,1,1-trichloroethane-induced liver toxicity, as indicated by an assay of liver function (bromosulfophthale in retention in plasma), but not an assay of liver damage (SGPT levels) (Klaassen and Plaa 1966). Other studies, using only serum enzyme levels to assay liver... 

The antioxidant and hepatoprotective actions of M. anka against acetaminophen (AAP)-induced liver toxicity have been investigated (Aniya et al., 1998). Their results show that M. anka prevents AAP-induced liver toxicity by both antioxidant action and the inhibition of AAP metabolism. Further antioxidant action of M. anka was studied in vitro and in vivo... 

Aniya, Y., Yokomakura, T., Yonamine, M., Nagamine, T., and Nakanishi, H. 1998. Protective effect of the mold Monascus anka against acetaminophen-induced liver toxicity in rats. Jpn. J. Pharmacol. 78(1), 79-82. 

Germander has been used as a remedy for weight loss and general tonic. Germander tea made from the aerial parts of the plant has been used for many cenmries. Twenty-six cases of germander-induced liver toxicity have been reported in Europe. A 55-year-old woman taking 1600 mg per day of germander became jaundiced after 6 months. Her bilirubin was... 

Another example of the increased susceptibility of patients with certain viral infections for dmg-induced mitochondrial dysfunction is the increased hepatotox-icity of highly active antiretroviral therapy (HAART) in HIV/HBV or HCV coinfected patients (Sulkowski et al. 2002 Wit et al. 2002). Certain viral proteins such as the HCV core protein or the HBV X protein disturb mitochondrial function (Rahmani et al. 2002 Korenaga et al. 2005 Piccoli et al. 2007), and, together with cytokines, could impair mitochondrial function and make HBV- or HCV-coinfected subjects more susceptible to HAART-induced liver toxicity. 

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,... 

Information is limited, but it would now seem prudent to consider warning patients taking isoniazid to limit their use of paracetamol because it seems that some individuals risk possible paracetamol-induced liver toxicity, even with normal reeommended doses. Pharmacokinetic studies suggest that it is possible that the risk is greatest shortly after stopping isoniazid. The risk may also be higher if paracetamol is taken late in the isoniazid dosing interval, partieularly in fast acetylators of isoniazid. More study is needed to elarify the situation. 

When monitoring concurrent use it is important to understand fully the implications of changes in total and free or unbound serum phenytoin concentrations. Where monitoring of free phenytoin levels is not available, various nomograms have been designed for predicting unbound phenytoin concentrations during the use of valproate. Bear in mind the evidence that the incidence of valproate induced liver toxicity may be increased, especially in infants. 

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