Detoxication metabolism

Jakoby, W.B., Bend, J.R., and Caldwell, J. (1982). Metabolic basis of detoxication Metabolism of functional groups (Academic Press, New York). 

As we have seen, the breakdown or detoxication (metabolism) of a chemical is carried out by enzymes. These biological catalysts are proteins that are produced with information encoded in DNA. If there is an error (known as a mutation) in the DNA code that holds the information, the enzyme (protein) that is produced may be faulty. Mutations occur naturally and are passed on from one generation to the next. Some are benign, others potentially lethal. An example of this is the mutation that causes the disease haemophilia, which was carried by Queen Victoria and which afflicted various male members of the royal families of Europe who were descended from her. 

Wolf, C.R. In "Metabolic Basis of Detoxication, Metabolism of Functional Groups" Jakoby, W.B. Bend, J.R. Caldwell, J. Eds Academic Press, 1982 Chpt. 1. 

Keywords Glutathione Redox Cysteine Drug detoxication Metabolism ... 

Toxication versus detoxication. Metabolism may be detoxication in many cases but sometimes it produces a more toxic or reactive metabolite. However, there may be more... 

Jakoby W, Bend JR, Caldwell J, eds. Metabolic Basis of Detoxication—Metabolism of Functional Groups. New York Academic Press, 1982. 

GST dimer complex is important not only for the understanding of the mechanism of detoxication metabolism but also for the development of new antibiotics. 

Many pesticides are not as novel as they may seem. Some, such as the pyre-throid and neonicotinoid insecticides, are modeled on natural insecticides. Synthetic pyrethroids are related to the natural pyrethrins (see Chapter 12), whereas the neo-nicotinoids share structural features with nicotine. In both cases, the synthetic compounds have the same mode of action as the natural products they resemble. Also, the synthetic pyrethroids are subject to similar mechanisms of metabolic detoxication as natural pyrethrins (Chapter 12). More widely, many detoxication mechanisms are relatively nonspecific, operating against a wide range of compounds that... 

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. 

Sites of metabolism. When a chemical reaches one of these, it is metabolized. Usually this means detoxication, but sometimes (most importantly) the consequence is activation. The organism acts upon the chemical. 

Fish show generally low HMO activities that are not strongly related to body weight. This may reflect a limited requirement of fish for metabolic detoxication they are able to efficiently excrete many compounds by diffusion across the gills. The weak relationship of HMO activity to body weight is probably because fish are poikilotherms and should not, therefore, have an energy requirement for the maintenance of body temperature that is a function of body size. In other words, the rate of intake of xenobiotics with food is unlikely to be strongly related to body size. 

The organophosphorons insecticides dimethoate and diazinon are mnch more toxic to insects (e.g., housefly) than they are to the rat or other mammals. A major factor responsible for this is rapid detoxication of the active oxon forms of these insecticides by A-esterases of mammals. Insects in general appear to have no A-esterase activity or, at best, low A-esterase activity (some earlier stndies confnsed A-esterase activity with B-esterase activity) (Walker 1994b). Diazinon also shows marked selectivity between birds and mammals, which has been explained on the gronnds of rapid detoxication by A-esterase in mammals, an activity that is absent from the blood of most species of birds (see Section 23.23). The related OP insecticides pirimiphos methyl and pirimiphos ethyl show similar selectivity between birds and mammals. Pyrethroid insecticides are highly selective between insects and mammals, and this has been attributed to faster metabolic detoxication by mammals and greater sensitivity of target (Na+ channel) in insects. 

Emphasis is given to the critical role of metabolism, both detoxication and activation, in determining toxicity. The principal enzymes involved are described, including monooxygenases, esterases, epoxide hydrolases, glutathione-5 -transferases, and glucuronyl transferases. Attention is given to the influence of enzyme induction and enzyme inhibition on toxicity. 

Resistance mechanisms associated with changes in toxicokinetics are predominately cases of enhanced metabolic detoxication. With readily biodegradable insecticides such as pyrethroids and carbamates, enhanced detoxication by P450-based monooxygenase is a common resistance mechanism (see Table 4.3). 

The oxidation of OPs can bring detoxication as well as activation. Oxidative attack can lead to the removal of R groups (oxidative dealkylation), leaving behind P-OH, which ionizes to PO . Such a conversion looks superficially like a hydrolysis, and was sometimes confused with it before the great diversity of P450-catalyzed biotransformations became known. Oxidative deethylation yields polar ionizable metabolites and generally causes detoxication (Eto 1974 Batten and Hutson 1995). Oxidative demethy-lation (0-demethylation) has been demonstrated during the metabolism of malathion. 

With aldicarb, primary metabolic attack is again by oxidation and hydrolysis. Hydrolytic cleavage yields an oxime and represents a detoxication. Oxidation to aldicarb sulfoxide and sulfone, however, yields products that are active anticholinesterases. Carbofuran is detoxified by both hydrolytic and oxidative attack. 

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