Metabolism induced toxicity

Dibromoethane is metabolized to active forms capable of inducing toxic effects by either of two systems-the microsomal monooxygenase system (cytochrome P-450 oxidation) and the cytosolic activation system (glutathione conjugation). Figure 2-3 provides an overview of the metabolism of... 

Sato A, Nakajima T. 1984. Dietary carbohydrate- and ethanol-induced alteration of the metabolism and toxicity of chemical substances. Nutr Cancer 6 121-132. 

The mechanism of benzene-induced toxicity appears to involve the concerted action of several benzene metabolites. Benzene is metabolized, primarily in the liver, to a variety of hydroxylated and opened-ring products that are transported to the bone marrow, where secondary metabolism occurs. Metabolites may induce toxicity both by covalent binding to cellular macromolecules and by inducing oxidative damage. Metabolites may also inhibit stromal cells, which are necessary to support growth of differentiating and maturing marrow cells. ... 

In addition to oxygen free radicals, other compounds such a clozapine, olanzapine and procainamide induce reactive intermediates [8, 9]. Clozapine and olanzapine bioactivation is thought to occur through a nitrenium ion [20] however clozapine but not olanzapine induce toxicity to neutrophils. This can lead to an immune-mediated depletion of neutrophils and their precursors (CFU-GM) [21]. Also, nonsteroidal antiinflammatory drugs (NSAIDs) have pro-oxidant radicals that when metabolized could cause oxidative stress [22]. 

VPA is also a nonspecific but weak inhibitor of the CYP-450 enzyme system, causing serum levels of other hepatically metabolized drugs to be increased. For example, concomitant use of VPA with diazepam, ethosuximide, or phenobarbital can increase the levels of these latter drugs. VPA may also cause an elevation in serum levels of CBZ s epoxide metabolite, possibly inducing toxicity. Usually, however, these changes are not clinically significant ( 367). 

Digoxin susceptible to alteration of gastrointestinal absorption. Digitalis toxicity may be increased by drug-induced electrolyte imbalance (eg, hypokalemia). Digitoxin metabolism inducible. Renal and nonrenal excretion of digoxin susceptible to inhibition. 

Forkert. P.G, Stringer, V. Racz. W.J. (1986b) Effects of administration of metabolic inducers and inhibitors on pulmonary toxicity and covalent binding by 1,1-dichloroethylene in CD-I mice. Exp. mol. Pathol., 45, 44-58... 

Foth, H. Role of the lung in accumulation and metabolism of xenobiotic compounds-implications for chemically induced toxicity. Crit. Rev. Toxicol. 25 165-205, 1995. 

Mortishire-Smith RJ, Skiles GL, Lawrence JW, Spence S, Nicholls AW, Johnson BA, Nicholson JK. Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of drug-induced toxicity. Chem Res Toxicol 2004 17 165-173. 

A variety of responses can be initiated by the direct interaction of metals with cellular components. Membrane damage and enzyme inhibition are examples of such a metal effect. Above a certain threshold concentration of metals in the cell, its physiological state is irreversibly changed (Van Assche et al., 1988). This response is reflected by an increase in capacity (activity under non-limiting substrate and coenzyme concentrations) of certain enzymes. This increase in capacity is generally called enzyme induction. These secondary, indirect effects of metals are considered to play an important role in the stress metabolism induced by toxic metal concentrations. 

Table 6-2. Enzymes of the intermediary metabolism induced after application of toxic concentrations of metals. Most of the experiments were performed on Phaseolus vulgaris cultivars, except those who are specially marked, which were performed on Glycine max (1) and on a zinc resistant (2) and a zinc sensitive (3) clone of Silene cucubalus (after Van Assche and Clijsters, 1990b, adapted).

Species Tested. In addition to the variation in susceptibility to chemically induced toxicity among members within a given population, there may be marked differences between species with respect to the relative potency of a given material to produce toxic injury. These species differences may reflect variations in physiological and biochemical systems, differences in distribution and metabolism, and differences in uptake and excretory capacity. 

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