Oxidative detoxication

The other major mechanism of pyrethroid resistance found in some field strains of Heliothis virescens was enhanced detoxication due to a high rate of oxidative detoxication, mediated by a form of cytochrome P450 (McCaffery 1998). Some strains, such as PEG 87, which was subjected to a high level of field and laboratory selection, possessed both mechanisms. Other example of pyrethroid resistance due to enhanced detoxication may be found in the literature on pesticides. 

At this time I was interested in the natural tolerance of houseflies to structural analogues of dieldrin and, with Harrison, I soon showed that whereas tolerance to cyclodienes was often related to oxidative detoxication and could be reduced or eliminated by benzodioxole synergists, dieldrin-resistance in houseflies did not respond to synergism and was apparently not a consequence of oxidative detoxication (33) Several laboratories (for their subsequent reviews see 34-36) confirmed the importance of oxidative biotransformations in insects and in 1964-5, at Slough, J. W Ray showed that microsomal preparations from houseflies and other insects contained cytochrome P450 (37) Thus, the links between insect and mammalian biochemical pharmacology were finally and firmly established. 

In the mid-1960s we showed firstly that the natural tolerance of houseflies to cyclodienes resulted mainly from oxidative detoxication (33 55) and secondly that another enzyme system, epoxide hydrase, converted certain dieldrin analogues into the corresponding trans-diols, (56,57) Interspecific differences in ability to attack enzymatically the unchlorinated ring systems of various analogues, either oxidatively and/or hydratively (if appropriate) can confer selective toxicity between insect species and also between insects and mammals (58) ... 

Butanal is readily metabolized to carbon dioxide by conversion to butyryl CoA and subsequent metabolism via the pathways of short-chain fatty acid oxidation. Detoxication by reaction with glutathione also occurs. Clearance is rapid and complete. 

In recent experiments mass spectrography has been used to identify 3-(2-hydroxy-4-chlorophenyl)-1,1-dimethylurea and 3-(2-hydroxy-4-chlorophenyl)-1 -methylurea in bean leaves as metabolites of monuron (Lee et al., 1973). This is, in the case of urea herbicides, experimental proof of the hydroxylating (oxidative) detoxication process, performed together with N-dealkylation by the microsomal oxidase enzyme system. 

This series of examples is by no means exhaustive, and others will be encountered in the later text. Although it is true that the great majority of oxidations catalyzed by cytochrome P450 represent detoxication, in a small yet very important number... 

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. 

The reaction is reversible and when the relative concentration of ethanol is high, alcohol dehydrogenase carries out the oxidation of ethanol => alcohol dehydrogenase is important in detoxication. 

Weiner H. Aldehyde oxidizing enzymes. In Jakoby WB, ed. Enzymatic Basis of Detoxication. New York, NY Academic Press 1980 261-280. 

Baez, S., Segura-Agmlar, J., Widersten, M., Johansson, AS., and Mannervik, B., 1997, Glutathione transferases catalyse the detoxication of oxidized metabohtes (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular... 

As in the case of propachlor mercapturic acid sulfoxide, the biological significance of xenobiotic mercapturic acids that contain oxidized sulfur is not known. Casida et al. (39) have reported that sulfoxidation of some thiocarbamate herbicides is a beneficial step in the detoxication process. However, cysteine conjugates can exhibit adverse biological activities. Smith (40) has reviewed work on the metabolism of the toxic principle in kale and has shown that C-S lyase action on S-methylcysteine sulfoxide produces the toxic principle. Virtanen ( ) has reviewed the processes in other plants that lead to the production of compounds with biological activity from -substituted cysteine sulfoxides. 

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