Liver necrosis reactive metabolites

Occasionally toxic compounds can directly damage the hepatic sinusoids and capillaries. One such toxic compound is monocrotaline, a naturally occurring pyrrolozidine alkaloid, found in certain plants (Heliotropium, Senecio, and Crotolaria species). Monocrotaline (Fig. 7.7) is metabolized to a reactive metabolite, which is directly cytotoxic to the sinusoidal and endothelial cells, causing damage and occlusion of the lumen. The blood flow in the liver is therefore reduced and ischemic damage to the hepatocytes ensues. Centrilobular necrosis results, and the venous return to the liver is blocked. Hence, this is known as veno-occlusive disease and results in extensive alteration in hepatic vasculature and function. Chronic exposure causes cirrhosis. 

Liver necrosis will occur in experimental animals treated with 3-methylcholanthrene. It seems likely that the metabolic activation takes place in situ rather than the reactive metabolite being transported from the liver. 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

The metabolite of bromobenzene that is believed to be responsible for the hepatic necrosis is bromobenzene 3,4-oxide. This reacts with liver cell protein, which causes cell death. The reactive metabolite can be detoxified by conjugation with glutathione or be detoxified by metabolism to a dihydrodiol by epoxide hydrolase. Pretreatment of animals with the enzyme inducer 3-methylcholanthrene decreases the toxicity. This is because it increases metabolism to the 2,3-oxide. This reactive metabolite is not as toxic as the 3,4-bromobenzene oxide readily undergoing rearrangement to 2-bromophenol. 3-Methylcholanthrene also induces epoxide hydrolase and so increases detoxication. 

Chloroform causes kidney damage (proximal tubular necrosis) and liver damage (hepatic necrosis). The mechanism is believed to involve metabolic activation of the chloroform in the kidney to produce phosgene, which is probably responsible for the toxicity. Both liver and kidney damage may be modulated by treating animals with enzyme inducers and therefore it seems likely that the liver damage is also mediated by a reactive metabolite. 

Much is known about the biochemical toxicology of hepatotoxicants, yet much remains to be learned. Hepatotoxicity resulting in either cell necrosis, fibrosis, or fatty infiltration is known to be a widespread phenomenon, potentially of importance to human health. It is caused by numerous drugs and environmental agents, and its incidence is expected to increase as confounding viral liver disease becomes more prevalent. Much is known about mechanisms based upon comprehensive studies with a few prototypical chemicals—namely, CCb, ethanol and acetaminophen—which support a convergence of varied primary effects on the ultimate failure of mitochondrial function and Ca2+ homeostasis. The extensive metabolic activity of the liver exposes its cells to a continuous flux of prooxidants. The importance of metabolic activation for the production of reactive metabolites is well-... 

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). 

Administration of bromobcnzcnc to rats causes severe liver necrosis. Extensive in vivo and in vitro studies indicate that the liver damage results from the interaction of a chemically reactive metabolite, 4-bromobcnzcnc oxide, with hcpatocytcs. " Extensive covalent binding to hepatic tissue... 

Acetaminophen is metabolized mainly by liver glucuronyl transferase to form the inactive conjugate. A minor pathway (via P450) results in formation of a reactive metabolite (N-acetylbenzoquinoneimine) that is inactivated by glutathione (GSH). In overdose situations, the finite stores of GSH are depleted. Once this happens, the metabolite reacts with hepatocytes, causing nausea and vomiting, abdominal pain, and ultimately liver failure due to centrilobular necrosis. Chronic use of ethanol enhances liver toxicity via induction of P450. 

Thus, extensive formation of reactive metabolites can cause severe ATP depletion and necrosis, or caspase activation and apoptosis (Fig. 7). The same compound can cause either of these two types of liver lesions depending on the circumstances. Indeed, the metabolic activation of the diterpenoids from the germander plant caused liver cell necrosis in treated mice (Loeper et al. 1994), but apoptosis in isolated rat hepatocytes (Fau et al. 1997). 

When rats are pretreated with 3MC, the liver becomes the major organ for toxicity (centrilobular necrosis) and alkylation by IPO (Figure 5 )(21 ) The fact that induction of the liver to produce more reactive metabolite does not cause increased alkylation and toxicity in the lung supports the concept that the pulmonary toxicity of IPO is due to in situ metabolic activation. 

As the dose of acetaminophen was increased, the incidence and severity of the liver necrosis in mice was increased ( ). However, an increase in toxicity would be expected to occur regardless of the mechanism of toxicity. Thus, the apparent correlation between the increase in covalent binding and the incidence of toxicity based solely on changes in the dose (12,17) is only trivial and does not indicate whether the toxicity is caused by the parent compound, the chemically reactive metabolite or some other metabolite. 

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