Liver necrosis metabolites

No changes in GTP and y-GT activity were recorded after repeated administration of the above compounds. Also, histopathological examination did not point to liver necrosis. Similar phenomenon detected earlier after repeated administration of monobromobenzene, was interpreted as a result of damage of the microsomal enzymatic system responsible for the appearance of active metabolites (ref. 22). 

Haloalkanes. Certain haloalkanes and haloalkane-containing mixtures have been demonstrated to potentiate carbon tetrachloride hepatotoxicity. Pretreatment of rats with trichloroethylene (TCE) enhanced carbon tetrachloride-induced hepatotoxicity, and a mixture of nontoxic doses of TCE and carbon tetrachloride elicited moderate to severe liver injury (Pessayre et al. 1982). The researchers believed that the interaction was mediated by TCE itself rather than its metabolites. TCE can also potentiate hepatic damage produced by low (10 ppm) concentrations of carbon tetrachloride in ethanol pretreated rats (Ikatsu and Nakajima 1992). Acetone was a more potent potentiator of carbon tetrachloride hepatotoxicity than was TCE, and acetone pretreatment also enhanced the hepatotoxic response of rats to a TCE-carbon tetrachloride mixture (Charbonneau et al. 1986). The potentiating action of acetone may involve not only increased metabolic activation of TCE and/or carbon tetrachloride, but also possible alteration of the integrity of organelle membranes. Carbon tetrachloride-induced liver necrosis and lipid peroxidation in the rat has been reported to be potentiated by 1,2- dichloroethane in an interaction that does not involve depletion of reduced liver glutathione, and that is prevented by vitamin E (Aragno et al. 1992). 

Other compounds cause liver necrosis because of biliary excretion. Thus, the drug furosemide causes a dose-dependent centrilobular necrosis in mice. The liver is a target as a result of its capacity for metabolic activation and because furosemide is excreted into the bile by an active process, which is saturated after high doses. The liver concentration of furosemide therefore rises disproportionately (chap. 3, Fig. 34), and metabolic activation allows the production of a toxic metabolite (Fig. 6.6). The drug proxicromil (chap. 5, Fig. 11) caused hepatic damage in dogs as a result of saturation of biliary excretion and a consequent increase in hepatic exposure. 

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. 

Mercaptopurine [6-MP] (Purinettiol) [Anrineoplasric/ Anri metabolite] Uses Acute leukemias, 2nd-line Rx of CML NHL, maint ALL in children, immunosuppressant w/ autoimmune Dzs (Crohn Dz) Action Antimetabolite, mimics hypo xanthine Dose Adults. 80-100 mg/m2/d or 2.5-5 mg/kg/d maint 1.5-2.5 mg/kg/d Peds. Per protocol 4 w/ renal/hepatic insuff on empty stomach Caution [D, ] Contra Severe hepatic Dz, BM suppression, PRG Disp Tabs SE Mild hematotox, mucositis, stomatitis, D rash, fever, eosinophilia, jaundice, Hep Interactions T Effects Wl allopurinol T risk of BM suppression W/ trimethoprim-sulfamethoxazole 4 effects OF warfarin EMS May falsely T glucose OD May cause N/V and liver necrosis symptomatic and supportive Meropenem (Merrem) [Anribioric/Carbapenem] Uses Intra-abd Infxns, bacterial meningitis Action Carbapenem 4 cell wall synth, a 3-lac-tam Dose Adults. 1 to 2 g IV q8h Peds. >3 mo, <50 kg 10-40 mg/kg IV q 8h 4 in renal insuff Caution [B, ] Contra fl-Lactam sensitivity Disp Inj 500 mg, 1 g SE Less Sz potential than imipenem D, thrombocytopenia Interactions T Effects W/ probenecid EMS Monitor for signs of electrolyte disturbances and... 

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... 

Figure 5. Acetaminophen overdose induces liver necrosis by formation of more hepatotoxin (metabolite A) than can be deactivated by glutathione conjugation (metabolite B). ...

Weak nonspecific inhibitor at common doses Potency may be modulated by peroxides Overdose leads to production of toxic metabolite and liver necrosis... 

Jewell H, Maggs JL, Harrison AC et al (1995) Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica 25 199-217 follow DJ, Mitchell JR, Zampaglione N et al (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11 151-169... 

Many types of liver injury are caused by a number of biochemical reactions of toxicants or their active metabolites. Such reactions inclnde covalent binding, lipid peroxidation, inhibition of protein synthesis, pertnrbation of calcium homeostasis, disturbance of biliary prodnction, and a variety of immunologic reactions. The types of liver injury from such biochemical reactions include steatosis (fatty liver), liver necrosis, cirrhosis, cholestasis, hepatitis, and carcinogenesis. The toxicants that cause these injuries are discussed in brief. 

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. 

Pretreatment of mice with phenobarbital increases the activity of the enzyme that catalyzes the formation of the reactive metabolite and thus accelerates the depletion of hepatic glutathione ( ), but apparently does not affect the enzymes that catalyze the formation of the sulfate or the glucuronide conjugates because it does not alter the biological half-life of the drug in mice ( ). Thus, pretreatment of mice with phenobarbital increases the proportion of the dose of acetaminophen that becomes covalently bound to liver protein by increasing Ratio A and increases the incidence and severity of the liver necrosis ( >20). 

The finding that cysteine can prevent the liver necrosis caused by acetaminophen in mice (17) led to the possibility that thio compounds might be useful as antidotes, provided that they are administered while the acetaminophen is being metabolized. Unfortunately, cysteine is a rather ineffective antidote except when it is administered intraperitoneally because it is incorporated into protein by all tissues of the body and thus is subject to a kind of first pass effect by these tissues. Most of the emphasis, therefore, has been toward the development of antidotes that serve as precursors of cysteine (such as methionine and N-acetylcysteine) and thus of glutathione or as alternative nucleophiles that combine with the chemically reactive metabolite. 

For example, consider bromobenzene as a cause of liver necrosis. Identification of metabolites formed from bromobenzene and their relationship to observed necrosis has been investigated, and a reactive intermediate of bromobenzene was implicated. Pretreatment with inducers and inhibitors of bromobenzene metabolites were used experimentally. This is represented by a general relationship shown in Figure 1 ( 3). In the case of bromobenzene, the reactive intermediate is 3,4-bromobenzene oxide. These studies require the efforts of biochemists and toxicologists, and the interdisciplinary nature of the investigation is readily seen. The joint effort promotes understanding. 

The acute toxicity of chlordane in rats increased when rats were fed protein deficient diets (Boyd and Taylor 1969). Chlordane treatment has also been demonstrated to enhance the hepatotoxic effects produced by carbon tetrachloride in rats, as indicated by its effect on SGPT levels, presumably by inducing the metabolism of carbon tetrachloride to its toxic metabolite (Mahon et al. 1978 Stenger et al. 1975). On the other hand, chlordane provided some protection against carbon tetrachloride-induced liver necrosis in rats, possibly by inducing a type of cytochrome P-450 with diminished ability to metabolize carbon tetrachloride to its toxic metabolite (Mahon et al. 1978). Pretreatment of rats with chlordane accelerated the metabolism of lindane, presumably by the same mechanism (Chadwick et al. 1977). 

There is evidence that the severe hypersensitivity reactions after isoniazid, characterized by fever, liver necrosis, and sometimes exanthema, occur mainly in rapid inactivators and are based on the accumulation of the metabolites acetylhydrazine and acetylisoniazid (Mitchell 1976 Brown 1976 Ellard et al. 1978 Ellard et al. 1981 Myles 1980). 

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