Increased detoxication

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. 

Cadmium, like zinc, binds to a protein, metallothionein, in the body The presence of cadmium increases the production of this protein by many times (the body increases detoxication, when threatened, which may be a reason for the development of tolerance). Although the binding removes the cadmium and effectively detoxifies it, the cadmium-protein complex is deposited in the kidneys and cadmium is eventually released, whereupon it seriously damages the organ. 

The biochemical and physiological mechanisms may be many, but resistance is often due to an insensitive target for the pesticide or to increased detoxication. 

Pyrethroids with Modified Chrysanthemate Esters. Newer pyrethroids incorporate optimized chrysanthemic acid components to retard detoxication by microsomal oxidases and these are esterified with a variety of optimized alcohol moieties therefore increasing persistence. 

The toxicity of chemicals to living organisms is determined by the operation of both toxicokinetic and toxicodynamic processes (Chapter 2). The evolution of defense mechanisms depends upon changes in toxicokinetics or toxicodynamics or both, which will reduce toxicity. Thus, at the toxicokinetic level, increased storage or metabolic detoxication will lead to reduced toxicity at the toxicodynamic level, changes in the site of action that reduce affinity with a toxin will lead to reduced toxicity. 

There is increasing evidence that microsomal monooxygenases with cytochrome P450 as their active center have a dominant role in the detoxication of the great... 

The problem of potentiation was discussed earlier (Chapter 2, Section 2.5). Potentiation is often the consequence of interactions at the toxicokinetic level, especially inhibition of detoxication or increased activation. The consequences of such potentiation may be evident not only at the whole animal level but also in enhanced responses of biomarker assays that measure toxicity (Figure 13.3). By contrast, biomarkers of exposure alone are unlikely to give any indication of potentiation at the toxicokinetic level. 

Although reduction of quinones is usually a detoxication pathway, there are examples such as mitomycin C in which the hydroquinone is more toxic than the quinone as shown in Figure 5.12 and this may increase the susceptibility of cancers that express high levels of NQO. In this case, the reduction of the quinone leads to the loss of methanol, which is the first step in the activation of this anticancer agent (20). 

Induction of P-450 Metabolism and Isoenzymes. When organisms are exposed to certain xenobiotics their ability to metabolize a variety of chemicals is increased. This phenomenon can produce either a transitory reduction in the toxicity of a drug or an increase (if the metabolite is the more toxic species). However, this may not be the case with compounds that require metabolic activation. The exact toxicological outcome of such increased metabolism is dependent on the specific xenobiotic and its specific metabolic pathway. Since the outcome of a xenobiotic exposure can depend on the balance between those reactions that represent detoxication and those... 

Koalas Phascolarctos cinereus) increase their glucose intake by 20% if they eat Eucalyptus spp. foliage, which requires conjugation reactions with glucuronic acid for excretion (Eberhard etal, 1975). Goats and sheep eat more of a toxic diet if given surplus food, which helps detoxication (Provenza, 2004). 

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