Human studies reactive metabolites

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-... 

Some explanations of the lower risk of agranulocytosis have been advanced after an in vitro cytotoxicity study (209). Like clozapine, olanzapine is oxidized to a reactive nitrenium ion by HOC1, the major oxidant produced in activated neutrophils. However, the olanzapine-reactive metabolite has a lower propensity to cause toxicity to human neutrophils, monocytes, and HL-60 cells than the reactive clozapine nitrenium ion. The lower toxic potential of the olanzapine reactive metabolite, in conjunction with the lower therapeutic plasma concentrations of olanzapine compared with clozapine, may help to explain this difference between the drugs. 

At high doses the interaction with protein can cause immediate damage to the liver (acute hepatitis). At lower doses interaction with DNA will lead to mutations in the genetic code which can cause cancer. Laboratory studies in experimental animals like rats have revealed that aflatoxin Bi can cause liver cancer, and the products of the reactive metabolites of aflatoxin can be detected in the blood of these animals. Furthermore the same metabolites have also been detected in the blood and urine of humans eating fungus-contaminated food in China, for example. Most recently a correlation has been shown between exposure to these fungal toxins, as indicated by metabolites of aflatoxins bound to protein in blood samples, and liver cancer in humans in China. 

Lopez Garcia, M. P. Dansette, P. M. Valadon, P. Amar, C. Beaune, P. H. Guengerich, E. P. Mansuy, D. Human-liver cytochrome P-450 expressed in yeast as tools for reactive-metabolite formation studies Oxidative activation of tienilic add by cytochromes P-450 2C9 and 2C10, Eur. J. Biochem., 1993, 213, 223-232. 

A second example is evident from the work of Singh et al.68 on the pyrazinone-containing thrombin inhibitor 2, which is associated with irreversible incorporation of radioactivity to human microsomal tissue and in vivo in the rat. Visual inspection of the structure as well as analysis in the DEREK program does not raise any concern with regards to the presence of structural alerts. However, mechanistic studies on reactive metabolite formation depict de novo metabolic routes of bioactivation on the latent pyrazinone-ring system, leading to the formation of reactive metabolites that adduct to GSH (Figure 6.6). 

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