Hepatotoxicity metabolite-related

Centrolobular necrosis is often a dose-related, predictable reaction secondary to drugs such as acetaminophen however, it also can be associated with idiosyncratic reactions, such as those caused by halothane. Also called direct or metabolite-related hepatotoxic-ity, centrolobular necrosis is usually the result of the production of a toxic metabolite (see Fig. 38-1). The damage spreads outward from the middle of a lobe of the liver. 

Tienilic acid- and dihydralazine-induced hepatitis are associated with antibodies against Cyp 2C9 [53] and Cyp 1A2 [54, 55], respectively. These are also the same cytochrome P450s that are responsible for the formation of reactive metabolites of these two drags. Anticonvulsant hepatotoxicity is associated with antibodies against rodent Cyp 3 A and related human enzymes such as thromboxane synthase [56, 57], It is interesting to note that cytochromes P450 are often the target of autoantibodies in idiopathic autoimmune hepatitis [58],... 

The reactions of nucleophiles with benzoquinone and related compounds can also be viewed as Michael reactions. Benzoquinone is one of the reactive metabolites of benzene, a solvent also associated with aplastic anemia (Fig. 8.14). A similar reactive metabolite is responsible for the hepatotoxicity of acetaminophen (Fig. 4.71), the most common cause of acute liver failure however, most of this reactive metabolite is detoxified by reaction with glutathione, and it is only when glutathione is depleted to approximately 10% of the normal level that significant toxicity ensues. 

Nefazodone is chemically related to trazodone. Its primary metabolites, hydroxynefazodone and m-cpp are both inhibitors of the 5-HT2 receptor. Nefazodone received an FDA black box warning in 2001 implicating it in hepatotoxicity, including... 

The most serious toxicities associated with carbamazepine use are idiosyncratic skin rashes, hematological disorders, hepatotoxicity, and teratogenicity (80). On the basis of studies with mice, teratogenicity is most likely related to formation of arene oxide and/or quinone-like metabolites of carbamazepine (83),... 

The mechanism of acute acetaminophen nephrotoxicity is related to the bioactivation of acetaminophen and/or its metabolites to highly reactive species which are capable of arylating renal macromolecules or generating reactive oxygen species. Acetaminophen hepatotoxicity is the result of conversion of acetaminophen to the reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI), which can covalently bind to hepatic macromolecules. It is less clear what role formation of NAPQI in the kidney plays in acetaminophen nephrotoxicity. In some species (e.g., the Fischer 344 rat) deacetylation appears to be an important biotransformation step in acetaminophen nephrotoxicity, while in other species (e.g., the CD-I mouse), bioactivation does not appear to require deacetylation of acetaminophen before the ultimate nephrotoxicant species is produced. Therefore, the role of NAPQI in acute acetaminophen nephrotoxicity might be species dependent. 

Clinical response to mercaptopurine is related to whole-blood concentrations of the metabolite 6-thioguanine, and hepatotoxic-ity is correlated with another metabolite, 6-methylmercaptopurme. Metabolic inactivation of azathioprine and mercaptopurine occurs by thiopurine S-methyltransferase, which exhibits genetic polymorphism. Enzyme-deficient patients are at greater risk of bone marrow suppression from these agents. Determination of enzyme activity may be necessary to determine which patients require lower doses of these agents. 

When chenodeoxycholic acid therapy was first introduced, there was some anxiety that this bile acid, or its bacterial metabolite lithcholic acid, might cause liver damage in man. This possible complication has not eventuated. Lithocholic acid is toxic to the liver in many animal species but in man, it is converted to sulfolithocholate and excreted (A5). Nevertheless, up to one-third of patients undergoing chenodeoxycholic acid treatment do show transient rises in serum levels of aspartate aminotransferase activity. The mechanism of this hypertransaminasemia is obscure, although it could possibly be related to lithocholate formation (D8). In any case, hepatotoxicity very rarely occurs at a clinically significant level (SI4). 

Related to carbon tetrachloride hepatotoxicity, aucubin is active only on in vivo assays [27], but not in vitro [49], This fact also is observed in other iridoids as loganin or catalposide [49], suggesting that the active agent could be a metabolite. The iridoid that has shown most important hepatoprotective activity is picroliv [88-98], and we emphasize that it could be interesting to assay catalpol in the showed assays for picroliv, and study the influence of these radicals on the hepatoprotective activity. Picroliv has been also assayed against aflatoxin Bi [81-87]. 

The toxic effects of busulfan are related to its myelosuppressive properties prolonged thrombocytopenia may occur. Occasional patients experience nausea, vomiting, and diarrhea. Longterm use leads to impotence, sterility, amenorrhea, and fetal malformation. Rarely, patients develop asthenia and hypotension. High-dose busulfan causes VOD of the liver in up to 10% of patients, as well as seizures, hemorrhagic cystitis, alopecia, and cataracts. The coincidence of VOD and hepatotoxicity is increased by its coadministration with drugs that inhibit CYPs, including imidazoles and metronidazole, possibly by inhibition of the clearance of busulfan and/or its toxic metabolites. 

Phomopsis leptostromiformis occurs in nature as a parasite and saprophyte of certain lupin plants, which are in turn associated with the animal disease lupinosis, a hepatotoxic condition characterized by severe liver damage and jaundice. Field outbreaks of lupinosis have been reported in grazing sheep, cattle, horses and pigs in Europe, Australia, New Zealand and South Africa where lupins are cultivated extensively for livestock feeding. Phomopsin A (11) and several other related metabolites are produced by P. leptostromiformis, in cultures grown on lupin seeds, liquid media or maize kernels. ... 

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