Detoxification and activation

Levine WG (1991) Metabolism of azo dyes implications for detoxification and activation drug. Metabol Rev 23(3-4) 253-309... 

While it might he sjttculated that a similar biphasic ctlcct on metabolism could occur whenever a lipophilic xenobiotic capable of forming a stable inhibitory complex is administered, lew cases have been well documented. Even in the case of MDP interactions, the isoform spec if icily of cither inhibition or induction has not been well defined. Since both detoxification and activation of chemicals are. to a greater or lesser extent, isoform-sped lie, more recent studies have focused on clarifying which iso forms of P450 arc involved and the importance of these isoforms in the biphasic response (Lewandow ski ei a .. 

WG Levine. Metaboilsm of azo dyes implication for detoxification and activation. Drug Metab Dispos 23 253-309,1937. 

Figure 3. Detoxification and activation of a thiophos-phate insecticide by cytochrome P-450.

General types of toxicity (three) metabolic detoxification and activation. 

Detoxification and Activation Reactions From an acute toxicity standpoint, the metabolism of pesticides by most organisms usually results in their conversion to products of lesser biological activity. There are several reasons v y such would be expected, not the least of which is the fact that the detoxification systems of living organisms have evolved for just such a purpose. Certainly, too, structure-activity relationships are usually so critical that toxicity, especially in the acute sense, is often greatly reduced or totally eliminated as the result of essentially any chemical transformation. Numerous examples of metabolic reactions leading to more-or-less complete pesticide detoxification could be cited, but the o-deethylation of chlorfenvinphos and the ester hydrolysis of carbaryl, both insecticides, are shown as somewhat representative examples (Figure 7). 

Cole D.J. Detoxification and Activation of Agrochemicals in Plants Pesticide Sciences 1994, 42, 209. 

The process of reabsorption depends on the HpophiHc—hydrophiHc balance of the molecule. Charged and ioni2ed molecules are reabsorbed slowly or not at all. Reabsorption of acidic and basic metaboHtes is pH-dependent, an important property in detoxification processes in dmg poisoning. Both passive and active carrier-mediated mechanisms contribute to tubular dmg reabsorption. The process of active tubular secretion handles a number of organic anions and cations, including uric acid, histamine, and choline. Dmg metaboHtes such as glucuronides and organic acids such as penicillin are handled by this process. 

The metaboHsm of a material may result in the formation of a transformation product of lower intrinsic toxicity than the parent molecule ie, a process of detoxification has occurred. In other cases, the end result is a metaboHte, or metaboHtes, of intrinsically greater toxicity than the parent molecule, ie, metaboHc activation has occurred. Some examples of detoxification and metaboHc-activation processes are given in Table 2. 

Table 2. Examples of Metabolic Detoxification and Metabolic Activation of Chemicals by Biological Systems...

The kidney is an important organ for the excretion of toxic materials and their metaboHtes, and measurement of these substances in urine may provide a convenient basis for monitoring the exposure of an individual to the parent compound in his or her immediate environment. The Hver has as one of its functions the metaboHsm of foreign compounds some pathways result in detoxification and others in metaboHc activation. Also, the Hver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the Hver (bile) and kidney (urine) as routes of excretion, the lung may act as a route of elimination for volatile compounds. The excretion of materials in sweat, hair, and nails is usually insignificant. 

Proton Pump Inhibitors and Acid Pump Antagonists retinoid X receptor (RXR) and is also activated by various lipophilic compounds produced by the body such as bile acids and steroids. PXR heterodimerized with RXR stimulates the transcription of cytochrome P450 3A monooxygenases (CYP3A) and other genes involved in the detoxification and elimination of the... 

Alexander55 identifies six major kinds of biodegradation mineralization, cometabolism, detoxification, transtoxification, activation, and defusing. Table 20.10 describes each of these processes and gives examples. 

Carotenoids have been found to exert numerous other effects of potential importance for the RPE. Carotenoids can activate transcription pathways (Ben-Dor et al., 2005 Kalariya et al., 2008 Palozza et al., 2006 Sharoni et al., 2004) for example, by activation of the antioxidant response element (ARE) (Ben-Dor et al., 2005 Sharoni et al., 2004). The ARE is an enhancer sequence responsible for the expression of many phase-II detoxification and antioxidant genes. Thus carotenoids may upregulate cellular antioxidant defenses. 

Kerklaan PRM, Zoetemelk CEM, Mohn GR. 1985. Mutagenic activity of various chemicals in Salmonella strain TA100 and glutathione-deficient derivatives On the role of glutathione in the detoxification or activation of mutagens inside bacterial cells. Biochem Pharmacol 34 2151-2156. 

Thus, exposure to any of these enzyme inducers concurrent with or after exposure to diazinon may result in accelerated bioactivation to the more potent anticholinesterase diazoxon. The extent of toxicity mediated by this phenomenon is dependent on how fast diazoxon is hydrolyzed to less toxic metabolites, a process that is also accelerated by the enzyme induction. Similarly, concurrent exposure to diazinon and MFO enzyme-inhibiting substances (e.g., carbon monoxide ethylisocyanide SKF 525A, halogenated alkanes, such as CC14 alkenes, such as vinyl chloride and allelic and acetylenic derivatives) may increase the toxicity of diazinon by decreasing the rate of the hydrolytic dealkylation and hydrolysis of both parent diazinon and activated diazinon (diazoxon) (Williams and Burson 1985). The balance between activation and detoxification determines the biological significance of these chemical interactions with diazinon. 

Efficacy and clinical use Naltrexone (Crabtree, 1984 Gonzalez and Brogden, 1988) is a pure opioid antagonist and has no analgesic activity. It is used for the treatment of opioid adverse effects, for opioid detoxification and as maintenance treatment for former addicts to avoid a relapse. In chronic opioid users, naltrexone may precipitate an acute withdrawal reaction. 

The above paragraphs summarize some of the studies in this area, and indicate that in preparing potentially useful biologically active agents of all classes, thiophene and ben-zothiophene rings may replace benzene, naphthalene or indole rings to produce active compounds which may be less toxic, have different physiological disposition and/or different modes of metabolism or detoxification, and thus impart desirable properties. 

Fig. 2. Schematic diagram delineating some of the multiple stages of mutagenesis and the interference by flavonoids. 1. Flavonoids induce apoptosis and enhance mutagen detoxification and extrusion from the cell. 2. Flavonoids interfere with the metabolic activation of mutagens and protect DNA by means of their antioxidative action. GST glutathione-S-transferase ROM reactive oxygen metabolites.

Two important reactions of arene oxides in animal tissue are (1) detoxification and (2) formation of conjugates of arene oxides with purine pyrimidine bases of DNA. For both of these reactions to take place, the arene oxide should have a certain intrinsic stability to survive an aromatization reaction. Reaction with the thiolate bond of glutathione is responsible for detoxification, whereas the extent of involvement of arene oxides in the nucleophilic reactions with nonpolarized nitrogen bases of DNA is directly related to their carcinogenic activity. 

---